Nitrous Oxide for the FRCA Primary

Nitrous Oxide Pharmacology

As always there is a lot to know about such a ‘commonly’ used drug in anaesthesia – certainly replaced with other less troublesome options (TIVA mitigating PONV, Remi infusions for titratable pain relief) but in the eyes of the royal college and abroad it remains a relevant drug.

Nitrous Oxide Physico-Chemical Properties

Name	Nitrous Oxide
Class	Inhalational anaesthetic
Chemical Make Up	[math]N_{2}O[/math] (two nitrogen molecules one oxygen molecule)
History	Discovered in 1772 by the English Chemist Joeseph Preistly – calling it phlogisticated nitrous air. Its utility in anesthesia – instead of recreational use, didnt make it till the 1790s by Humphry Davy identifying its pain relieving potential who struggled to utilise it safely, and then for dental anaesthesia by Horace wells
Isomer Status	Nil
Colour/Appearance	Clear Colourless vapour – with a slight sweetness Denser than oxygen (heliox being less dense)
Pin Index of Nitrous Oxide	3 – 5
Stability/Storage	French Blue Cylinders Liquid and Gas E Size = 1800 Litres (on the back of your gas machine) 4400KPa at 20 °C Filling ratio (how much you put in vs how much you could put it) 0.75 in the chilly British climes 0.67 on a tropical Costa Rican trek Below its critical temp, it is in liquid and gas state.
Manufacturing	Ammonium nitrate (fertiliser) heated to 250 °C NH4NO3 >>> N2O + 2 H2O But can end up contaminated with other molecules including ammonia (NH3)/ nitrogen dioxide (NO2) and nitric acid (HNO3) It undergoes post heating processing to remove these contaminants.
Molecular weight	44g/mol
Climate	Nitrous oxide is a significant contributor to UK green house gas effect, its global warming potential 310 (desflurane 2540) Sevoflurane (~130)

Chemical Structure of Nitrous Oxide

N≡N-O

Physico-Chemical Properties

Nitrous Oxide Boiling Point	-88.5°C
Nitrous Oxide Saturated Vapour Pressure (@20°C)	5200KPa (52 Bar)
MAC of Nitrous Oxide	105%
Blood:Gas Solubility Coefficient Nitrous Oxide	0.47
Oil:Gas Solubility Coefficient Nitrous Oxide	1.4
Critical Temperature	36.5 °C
Critical Pressure	72 Bar
Maximal pollution level tolerable	100PPM
Comparative diffusion rate	16x more rapid than O2 crossing the alveolar membrane

Nitrous Oxide Pharmacodynamics & Side Effects

Mechanism of Action	Activity at many receptors – NMDA, dopamine, alpha 1 and 2 and opioid receptors. NMDA Receptor Antagonism Kappa Receptor activation in the Peri aqueductal grey matter (mid-brain)
Chief Effect / Actions	Analgesic Hypnotic Whipped cream propellant Drag Racing Propellant
Dose	More = more analgasesia, Too much = hypoxia
Cardio-Vascular Side Effects	Headline: Minimal, does bolster SNS slightly, which balances out the myocardial depression – unless you’ve a diseased heart. Chronotropy : Inotropy : Direct Myocardial depressant Dromotropy : Lussitropy : Bathmotropy : Coronaries: Systemic Vascular Resistance: Cardiac Output:
Respiratory Side Effects	Rate – Increased Depth – Decreased (minute volume and PACO2 unaltered) Parenchymal effects: Raises PVR further in Pulmonary hypertension patients In high dose may inhibit hypoxic pulmonary vasoconstriction Non-irritant
Central Nervous System Side Effects	ICP : Raised Cerebral Vasculature: Dilated CMRO2: depressed Seizure Threshold : n/a Nausea and vomiting: +++
Gastro-Intestinal Side Effects	PONV in up to 40% of patients
Renal Side Effects
Metabolic/MSK: Side Effects	No NMB interaction
Obstetric	NO Uterine hypotonicity
Nitrous Oxide Toxicity	Abuse leads to significantly altered DNA synthesis Any dose alters DNA synthesis. Its use can lead to changes in: Bone Marrow – Altered synthesis of high turnover cells 1. Megaloblastic changes with brief (hours) exposure, (seen 12h post N2O) 2. Agranulocytosis with chronic exposure. Spinal Cord > Sub acute combined degeneration of the cord 1. Dorsal column of spinal cord – sensory/proprioceptoive 2. Lateral Column loss (motor tracts) Potentially teratogenic in rats Mechanism of Nitrous Oxide Toxicity The Cobalt Ion on a vitamin B12 molecules is oxidised by N2O B12 normally works as a co-factor for methionine synthase Methionine synthase ultimately involved in the synthesis of DNA and precursors of that (thymidine, tetrahydrofolate, methionine) ‘Treatment for nitrous oxide excess is administering folinic acid’ Interestingly the impaired methionine synthase leads to higher homocystiene concentrations – and there is a potential correlation between these increased levels and increase post operative myocardial ischaemic events! This was initially suggested with the ENIGMA-1 trial, and subsequently refuted by the ENIGMA-2 Trial

Nitrous Oxide Pharmacokinetics

Absorption	Whilst not impossible to swallow, the GI surface area is low relative to the Lung – onset time and peak plasma concentration will be low.
Distribution	Perfusion dependent.
Metabolism Remember: Phase I : [oxidation, reduction, hydrolysis] (more cytochrome action here) Phase II: [conjugation, glucoronidation, acetylation, sulphylation]	Not Metabolised.
Elimination	Almost entirely via the lungs (and a tadge via the skin, and by gut bacterial of all things)

Nitrous Oxide in Practical Anaesthesia

Introduction and Episode Overview

[00:00–01:25]

Key points:

• Nitrous oxide (N₂O) is an anaesthetic and analgesic gas, not a true volatile agent
• Also known as laughing gas or, historically, “phlogisticated nitrous air” (Joseph Priestley)
• Once a cornerstone of anaesthesia (hence “gas man” and “passing the gas”)
• Now progressively displaced due to better agents and concerns about global warming potential

Please listen carefully.

Hello, Team Anaesthesia. Welcome to Gas, Gas, Gas. This is the best anaesthetic science podcast for the FRCA Primary exam. Our goal is to fill your brain with all this highly useful information. Now, you might be in the gym right now, commuting, or ironing your scrubs, and there’s no judgement here. Gas, Gas, Gas will prime your brain for the monsoon of knowledge you need to imbibe. But regardless, the revision is eventually going to end. But for now, expect facts, concepts, model answers, and the odd tangent. Now remember to check out the website, that’s gasgasgas.uk. There are show notes there with all the detail, plus links to foundational reference papers and anything else useful I find for you guys. Anyway, buckle up, get ready for your mind to be bent into a new shape, and let’s get on with the show.

Hello everyone, and welcome to yet another episode of Gas, Gas, Gas. Today we are taking a look at nitrous oxide, laughing gas, or, depending on your era of working, you could call it phlogisticated nitrous air, if you’re perhaps called Joseph Priestley. We’ll get into that in a minute. Why are we doing nitrous oxide? Well, technically it’s a vapour. Technically it is an anaesthetic and analgesic gas. It’s not quite really a true volatile in the volatile anaesthetic agent sense of the word. If you had a liquid of nitrous oxide knocking around, it would probably start boiling off relatively rapidly.

We use it in anaesthesia. It probably gets to go in the chapter on volatile anaesthetics and gases. Once upon a time a cornerstone of anaesthesia, hence the label “gas man” in times gone by, or “passing the gas”. Nitrous has been progressively displaced by better agents, especially when we consider our understanding of the global warming potential for nitrous oxide and the fact that we’re not using it to speed up the onset or offset of agents if we’re doing TIVA. Now I’m sure there are lunatics who do a total intravenous anaesthetic and then give someone a bit of nitrous as well. They probably only come out when there’s a full moon.

We’re going to explore the full pharmacology of nitrous oxide in the context of what you are expected to know for the exam. And then we’re going to explore a few of the properties of nitrous when practically applying it in an anaesthetic that are interesting and certainly examinable.

Single Best Answer Question

[02:19–03:51]

Drug Classification and History

[03:51–05:20]

Key points:

• Classification: Inhaled anaesthetic agent; Class C drug in UK
• Molecular formula: N₂O (two nitrogens, one oxygen)
• Discovered 1772 by Joseph Priestley
• Humphrey Davy noted analgesic potential in 1790s
• First used for dental anaesthesia by Horace Wells in early 1800s
• Not an isomer

Right, so nitrous oxide pharmacology. What class of drug is nitrous oxide? Well, it’s an inhaled anaesthetic agent or, in the eyes of the British totalitarian state of drug classifications, it’s now a Class C drug. So possession of it is seemingly a criminal offence. This came about because all the kids and a lot of the adults have been smashing nitrous oxide for a laugh and leaving those ampoules lying around everywhere on the streets.

We’re going to get into why nitrous oxide isn’t a completely innocuous gas to be inhaling. But if we roll back ourselves in time, this molecule of two nitrogens and one oxygen was discovered in 1772 by the English chemist Joseph Priestley. And he did indeed call it phlogisticated nitrous air.

Now, initially, everyone just thought it was a good laugh, quite literally, and it was used for recreational purposes. Its utility in anaesthesia didn’t start creeping in for about 20 years. Humphrey Davy in the 1790s noted it certainly had pain relieving potential. It was then used in the early 1800s for dental anaesthesia by Horace Wells and we’ve been using it ever since. It is not an isomer, you’ll be happy to know.

Physical Properties and Storage

[05:20–07:47]

Key points:

• Appearance: Clear, colourless, slightly sweet, non-irritant vapour
• Critical temperature: 36.5°C (vapour below this, gas above)
• Storage: French blue cylinders containing liquid and gaseous N₂O
• E-size tanks: 1,800 litres when full
• Tank pressure: 4,400 kPa at 20°C
• Pipeline pressure: 4 bar
• Filling ratio: 0.75 (UK), 0.67 (tropical climates)
• Pin index: 3 and 5

How does it look? Well it’s a clear and colourless vapour. It is a vapour unless it is above its critical temperature. Okay, remember that. Remember, a vapour is a vapour below its critical temperature. If you take nitrous oxide as a gas and heat it to above 36.5 degrees, it becomes a gas. It can’t be a vapour anymore. Why do we care about that? Well, if it’s really hot and you try and compress it, it won’t become a liquid again. Whereas below that critical temperature, if you squidge it down, eventually it will become a liquid because it doesn’t have quite enough energy to resist becoming a liquid. At least that’s how I imagine it in my mind.

It is slightly sweet and it is non-irritant. That’s why you can use it for labour analgesia. Ambulance crews use it when people have snapped something important. The density of nitrous oxide is quite high, higher than oxygen and certainly higher than heliox which is the least dense of those three.

Now nitrous oxide is stored in French blue cylinders and this can either be a cylinder on the back of your anaesthetic machine or a bunch of cylinders in a manifold somewhere on your hospital site that delivers nitrous oxide through pipelines at four bar to where it is required in the hospital complex. It is French blue cylinders and within that cylinder you will find liquid and gaseous nitrous oxide. On the back of the anaesthetic machine you’ll find E-size tanks that contain 1,800 litres of nitrous oxide when full. The pressure in that tank will be 4,400 kilopascals at 20 degrees.

An important thing to note with tanks of nitrous, they’re not completely filled up. And that’s because if you heat them up a bit too much, much more of it’s going to want to be in its gaseous phase. You run the risk of tanks exploding. So in the UK, they are 75% full. And when we say this, if you took a tank and filled it all with water, and then took 25% of that water out, that’s the equivalent of saying that there’s 75% of it has liquid nitrous in it. The rest is empty. It’s filling ratio.

In tropical places, like if you’re perhaps administering a nitrous oxide volatile anaesthetic on a lovely Costa Rican beach, your filling ratio in that tank is 0.67 and that’s because generally speaking it’s a warmer place, it’s going to want to have more gas than liquid comparatively to Britain. You want to fill it up a bit less to reduce the chances of a rapid unscheduled disassembly of that tank of nitrous oxide.

The pin index of nitrous oxide is 3 and 5. Pin indexes mean that you can’t accidentally put an oxygen tank where the nitrous tank should go on the back of your anaesthetic machine. Because as you can imagine, if in an emergency and you’ve run out of oxygen in the pipelines in your hospital and you switch to that emergency tank of gas on the back of your anaesthetic machine to keep that patient safe and oxygenated, and it turns out you’re administering 100% nitrous oxide, well then you’re going to have a very blue patient and you won’t really know why. And that’s why pin indexes exist.

Manufacture of Nitrous Oxide

[08:17–09:48]

Key points:

• Made by heating ammonium nitrate to ~250°C
• Products: N₂O + H₂O
• Contaminants requiring removal: ammonia (NH₃), nitrogen dioxide, nitric acid, carbon dioxide
• Molecular weight: 44 g/mol

Now for some weird reason, they might ask you in the exam how nitrous oxide is made. You take ammonium nitrate and that’s fertiliser and you heat it up to about 250 degrees C and this liberates nitrous oxide and water from ammonium nitrate. Now I feel and you probably feel that ammonium nitrate doesn’t sound particularly good for humans and if you keep this imagination going in your mind you will note that upon heating ammonium nitrate you won’t just get nitrous oxide and water. That would be too easy.

You also end up with other contaminants like ammonia, NH₃. Bit bad for your health. And nitrogen dioxide. We don’t like that coming out of diesel vehicles so we probably don’t like putting that into people. And nitric acid alongside some carbon dioxide. It undergoes post-processing with acids and bits and bobs to remove these contaminants. And if they’re asking you about how nitrous oxide is made in the exam it’d be pretty cruel to ask you how they decontaminate. They probably just want you to know that it’s made with ammonium nitrate heated up. Extract the nitrous oxide. There are contaminants that are removed in post-processing to achieve near pure nitrous oxide.

Its molecular weight is 44 grams per mole, so it’s really light. But remember, it is two nitrogen molecules and one oxygen molecule. It’s quite small.

Environmental Impact and Global Warming Potential

[09:48–11:44]

Key points:

• Global warming potential (100-year CO₂ equivalent): N₂O = 310×
• For comparison: Desflurane = 2,540×; Sevoflurane = 130×
• Some hospitals have decommissioned N₂O pipelines due to leakage
• Alternative for obstetrics: remifentanil PCA

Why is nitrous oxide falling out of favour? Well, for a number of reasons, but the big one is its implications for heating the planet as a greenhouse gas. That is, its comparison to 100 years of an equivalent quantity of carbon dioxide in the atmosphere. So it’s 310 times more greenhouse gassy than CO₂. And to contextualise that, desflurane is leading the charge at 2,540 times as bad as that equivalent volume of CO₂. And sevoflurane is at 130. So avoiding it is not the end of the world. It’s a good thing to do.

One of the hospitals near me managed to eradicate its use of nitrous oxide at the anaesthetic machine. And noting that the administration on the maternity side of things was coming from a different manifold, they realised that they were still using nitrous oxide despite not putting it into patients. And the pipelines were leaking nitrous. So they were replacing these tanks and it was just slowly oozing out into the atmosphere, not even going through a patient first.

So they decommissioned the pipelines and now that hospital itself still allows nitrous oxide. It’s just on the back of the anaesthetic machines and you can choose to turn it on and use it if you have a particular indication. You know, a gas anaesthetic in a pretty grumpy child where actually if you sneak some nitrous at them and gently bamboozle them and then whack the sevo on, you get them off to sleep nice and smoothly. Now I’m not saying that that is the only way to get a slightly grumpy child off to sleep with gas but it does seem to be helpful.

A contrary argument for nitrous and climate is us as anaesthetists being terribly conscientious and trying to reduce our use. And then you go on to the maternity wards and, you know, women with minute volumes of 10 or 12 litres per minute absolutely huffing away on nitrous oxide for, you know, 12 hours at a time, having an awful rotten time of it. And then you just think, what’s the absolute point? Every little helps. And maybe your project in your hospital to mitigate that would be remifentanil patient-controlled analgesia in obstetrics, works really nicely.

Physicochemical Properties

[11:44–14:11]

Key values:

• Boiling point: -88.5°C
• Saturated vapour pressure: 5,200 kPa at 20°C
• MAC: 105% (requires hyperbaric conditions to achieve 1 MAC)
• Oil:gas solubility coefficient: 1.4 (low potency)
• Blood:gas solubility coefficient: 0.47 (rapid equilibration)
• 16× more soluble than oxygen across alveolar membrane
• Critical temperature: 36.5°C
• Critical pressure: 72 bar
• Workplace exposure limit: 100 ppm

Cool, so physicochemical properties of nitrous oxide. Again, you know, you’d be banging your head against a brick wall thinking, why do I have to know these numbers? And you do have to know these numbers, but only really for the exam. And it is kind of interesting for me, at least, to look back at this, having learned all these numbers once upon a time, and think, oh yeah, I’ve got an approximation in my mind of where nitrous sits within these other gases.

Anyway, it boils at minus 88.5. So if you have liquid nitrous and you tip it out at atmospheric pressure in a warmish place, it’s just going to start boiling away, becoming a vapour, unless you’re in a particularly warm place that’s greater than 36.5 degrees C. The saturated vapour pressure of nitrous oxide is really high, 5,200 kilopascals at 20 degrees C.

The MAC of nitrous oxide, now this is one to bend your brain slightly, 105%. So to achieve one MAC of anaesthesia with nitrous oxide, you have to somehow get the patient 105% full of nitrous, which means obviously you’re displacing all that oxygen. How do you achieve that? Well, you have to put the patient in a pressure chamber in order to therefore give yourself more manoeuvring room to administer more kilopascals of nitrous and get it in their brain. You can therefore think that it’s probably not very potent and its oil gas solubility is 1.4. Lower number of the oil gas solubility, less potent, therefore.

But its blood gas solubility coefficient is 0.47. So it is quite uninterested in remaining in the plasma when administered. So whilst nitrous oxide is really keen to get into the blood, it’s even more keen to get out of the blood. So it is comparatively 16 times more interested in crossing the alveolar membrane than oxygen is. And this leads to some interesting effects which we’re going to talk about after we’ve gone through all the boring numbers.

You should be able to tell me by now what the critical temperature of nitrous oxide is because I’ve said it several times. It’s 36.5 degrees C and its critical pressure 72 bar. Hey whoa, one second there, what on earth is critical pressure you say? So critical pressure is the pressure required to reliquify that gas vapour borderline state. So if we’ve got our nitrous oxide at 36.5 degrees C which is that cutoff point between vapour and gas. We would need to exert 72 bars of pressure to shift that back to being a liquid.

Last but not least, from an environmental exposure perspective, within that anaesthetic room or that maternity room, 100 parts per million of nitrous oxide is considered safe. Above that, you start having issues again. We will get to the issues.

Pharmacodynamics: Mechanism of Action

[14:11–16:15]

Key points:

• NMDA receptor antagonist (like ketamine)
• Effects on: dopamine receptors, α₁ and α₂ adrenoceptors, opioid receptors
• Opioid activity in periaqueductal grey matter (PAG) of midbrain
• Dopamine effects may contribute to PONV
• Chief effects: Analgesic, hypnotic
• Other uses: Drag racing (NOS), whipped cream propellant

So how does it work? What are the pharmacodynamics? What does it do to the body? So the mechanism of action of nitrous has been bandied around over the years and it seems to have accumulated a number of different mechanisms, so it probably actually gets up to mischief in many a place. It is certainly an NMDA receptor antagonist like ketamine, etc. But it was also noted to have effects on dopamine receptors, alpha-1 and alpha-2 adrenoceptors, and opioid receptors.

From an opioid perspective, it seems to have some activity in the periaqueductal grey matter of the midbrain. Remember that PAG place, and that’s where you find quite a significant density of opioid receptors and it’s a site of pain modulation. There are some suggestions in some of the literature I’ve read that the effects on dopamine receptors are one of the causes of the significant post-operative nausea and vomiting problem that nitrous oxide has.

What are its chief effects and actions? Well it is an analgesic, it is certainly hypnotic, but also its actions involve making drag racing cars go really proper fast because you can squirt it into fuel mixes in modified engines and make the engines go better. And also, if you are propelling whipped cream onto a cake or into a cream eclair, you would use nitrous oxide compressed to deliver that. That’s where all the kiddies were getting their hands on nitrous oxide. It goes in these ampoules that are used to administer whipped cream to things.

Dosing and Anaesthetic Machine Safety Features

[16:15–16:41]

Key points:

• Linear dose-response: more N₂O = more analgesia/anaesthesia
• Limit: Cannot administer hypoxic mixture
• Chain link mechanism on flowmeters: N₂O on = O₂ on; O₂ off = N₂O off
• Minimum oxygen delivery: 30%

Now the dose, what is the dose of nitrous oxide? Well, it’s somewhat linear. The more you give, the more pain relief you get and the more anaesthesia you get. Too much, though, equals hypoxia. You can’t find yourself administering a hypoxic mixture. You can’t do that. There’s a chain link guard that means that if you turn the nitrous on, it turns the oxygen on. And if you try and turn the oxygen off, it turns the nitrous off. Especially on flowmeters. If you’ve got those in your anaesthetic machine still, have a fiddle. They’re linked together. Now you can often nudge slightly as the chains get looser to administer a slightly more potent mix, but generally speaking, it won’t let you go below 30% oxygen. Nor will the anaesthetic machines generally.

Side Effect Profile

[16:41–18:11]

Key points:

• CVS: Mild sympathetic stimulation + direct myocardial depression (caution in cardiac patients)
• Respiratory: ↑Rate, ↓Depth; minute volume and PaCO₂ unchanged
• Pulmonary: ↑Pulmonary vascular resistance (avoid in pulmonary hypertension)
• CNS: ↑ICP via cerebral vasodilation; ↓CMRO₂
• Not used in neurosurgery
• PONV: Up to 40% incidence
• Does NOT affect seizure threshold
• Does NOT interact with neuromuscular blocking agents
• Does NOT reduce uterine tone (useful in crash section GA)

What about the side effect profile of nitrous oxide? So overall, it doesn’t cause that much mischief. But from a cardiovascular perspective, it slightly excites your sympathetic nervous system and has a direct myocardial depressant effect. So if your heart’s a bit knackered, maybe you need to just think twice about using nitrous.

From a respiratory perspective, I bet you can imagine what it does to your rate and depth. It increases your rate and it decreases your depth. Therefore, your minute volume, and your arterial CO₂ tension are generally unchanged. From a lung parenchyma effect, it raises pulmonary vascular resistance. And if you have a patient with pulmonary arterial hypertension, it might be sensible to avoid nitrous oxide.

Nitrous raises intracranial pressure by causing cerebral vasodilation. It does reduce cerebral oxygen consumption, but generally speaking, it is not used for neurosurgery. And so the chief CNS side effect is increased nausea and vomiting and that’s seen in up to 40% of patients. It doesn’t mess with your seizure threshold. Nitrous oxide does not synergistically interact with neuromuscular blocking agents and it does not cause a reduction in uterine tone and this is why it is sometimes reached for in a crash section GA type jobby where you’re trying to get anaesthetic depth quickly. Nitrous oxide is your friend if that’s the way you roll.

Toxicity and Vitamin B12

[18:11–22:43]

Key points:

• Class C drug – recreational abuse causes hypoxic seizures
• Mechanism: Irreversibly oxidises cobalt ion on vitamin B12
• B12 is cofactor for methionine synthetase → impaired DNA synthesis
• Affected precursors: Thymidine, tetrahydrofolate, methionine
• Acute effects: Megaloblastic changes on FBC within 12 hours
• Chronic effects: Agranulocytosis, subacute combined degeneration of cord
• SACD affects: Dorsal columns (sensory/proprioception) + lateral columns (motor)
• Treatment: Folinic acid (spinal cord injury is irreversible)
• Homocysteine levels increase (substrate accumulation)
• ENIGMA-1: Possible correlation with perioperative MI
• ENIGMA-2 (larger RCT, Lancet): No association found

What about toxicity? We all know that it’s toxic and is a drug of abuse. So obviously I’ve mentioned it’s now a Class C drug and people have been using it in the streets. People can end up with tanks of nitrous oxide and they fill them up with balloons and huff away on that. But actually they trigger seizures with hypoxic brains when they inhale a load of nitrous out of a balloon repeatedly. They might start laughing, they might start briefly tripping, but it’s because their brain is starved of oxygen. It’s generally bad for you. I think there are, you know, mentions in the literature of people having brain injuries following those hypoxic events. And I’m sure you might have come across, I have definitely come across, people who get their hands on nitrous oxide with an ambulance crew, because actually, secretly deep down, they’re abusing it, and then they don’t let go. And you get them in A&E, and they are literally this possessed demon puffing away on nitrous oxide, desperate for it. And you know, I suppose some people enable that, and other people would just go and unplug it from the wall. I know which sort of person I am because they’re having a drug that’s not prescribed, demanding it and, you know, it’s injurious.

Why is it injurious? So it alters DNA synthesis, right? And that sounds bad because chemotherapy drugs alter DNA synthesis and you’re right. And therefore, you can probably assume that when you give someone chemotherapy agents, what’s the thing that we always warn patients about? Neutropenia. So when you briefly give someone nitrous oxide for an anaesthetic, maybe for a couple of hours, if you do a full blood count in 12 hours time and you’ve done a full blood count at time zero, you will see megaloblastic changes in their full blood count courtesy of altered DNA synthesis. And remember, when you impair DNA synthesis in a human, high turnover sites are affected chiefly and your bone marrow generating blood cells is a high turnover site. If you are chronically exposed to nitrous oxide, you will end up potentially with an agranulocytosis state, really bad for your health.

With chronic exposure of nitrous oxide, you can also end up with spinal cord issues. Chiefly, subacute combined degeneration of the cord. You end up with dorsal column pathology and lateral column pathology. So sensory and proprioceptive changes and then motor tract changes respectively.

How does this all come about? It sounds very extreme. So nitrous oxide oxidises the cobalt ion that you find on a vitamin B12 molecule. It irreversibly oxidises that cobalt ion, meaning your B12 is of no use to you at that point in time. We know how patients with B12 deficiency present. They can have a macrocytic anaemia picture, tingly hands, and peripheral neuropathy. B12 normally works as a cofactor for methionine synthase. Methionine synthase ultimately is involved in synthesis of DNA and its precursors, particularly thymidine, tetrahydrofolate and methionine. This impaired synthesis state leads to the upsets described. Bone marrow changes, spinal cord changes.

Treatment for this nitrous oxide excess, you can give patients folinic acid. This will help nudge them along. But once you’ve got particularly the spinal cord injury, that’s somewhat irreversible. And again, if you look in the papers, there are some people who now are sort of in a permanent toxic kind of mucked up state from nitrous oxide abuse.

A third concern for nitrous oxide that has been cast into the shadows: if you inhibit an enzyme we all know that that leads to a reduction in the product but also an increase in the substrate, i.e. the thing that goes into that enzyme to come out being something else. That substrate is homocysteine and again if you were to check homocysteine levels at time zero and time 12 you’ll see a change when you use nitrous oxide.

And there had been suggestion that there was a correlation between this increased level of homocysteine and myocardial ischaemic events. And two trials to try and identify if this is or is not the case. ENIGMA-1 and ENIGMA-2. ENIGMA-1 found that there was a possible correlation between nitrous oxide use and perioperative myocardial events. ENIGMA-2, bigger randomised control trial, found that there was not an association. So go nuts guys with all those patients with dodgy hearts. There’s a link to the paper in the show notes. It was published in The Lancet.

Sponsor Message: Teach Me Anaesthetics

[22:47–24:09]

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Pharmacokinetics: ADME

[24:09–25:34]

Key points:

• Absorption: Rapid via lungs; GI route impractical
• Distribution: Perfusion-dependent (like all volatiles)
• Metabolism: None
• Elimination: Almost entirely via lungs (trivial amounts via skin/gut bacteria)

What about the pharmacokinetics, i.e. what the body does to the drug? And remember, when doing this bit in the exam, break it down into absorption, distribution, metabolism and elimination, because it’ll just come across better.

Now, absorption of nitrous oxide. When it goes through the lungs, we’ve already established there’s rapid absorption. Now, you can’t really drink nitrous oxide, because if you were to somehow imbibe liquid nitrous, it would expand quite a lot inside you and be very bad for your health.

And if you were to pursue swallowing nitrous oxide as a gas, which, you know, you could choose to do, I don’t think you would perhaps have the same quality of anaesthesia and analgesia, likely because the GI surface area is quite low, and your onset time and peak plasma concentrations to achieve those sufficient effects. You’re just not going to cut the mustard, so perhaps just inhale it and don’t try to swallow nitrous oxide.

Distribution of nitrous oxide is perfusion dependent, as all volatiles are. It’s going to want to go and displace itself into areas with high cardiac output, at least initially, until you equilibrate that nitrous oxide throughout your patient. It is not metabolised, not a jot, and elimination-wise, it is almost entirely eliminated via the lungs. Although some boffins have found that a little bit comes out via the skin and gut bacteria anaerobically utilise it. But that is really small fry and don’t even think about trying to remember that for the exam.

The Concentration Effect and Second Gas Effect

[25:34–30:02]

Key points:

• Concentration effect: Rapid alveolar uptake of carrier gas draws more gas into alveolus
• Second gas effect: Consequence of concentration effect; increases alveolar concentration of volatile
• Result: Faster onset of anaesthesia with co-administered volatile
• Diffusion hypoxia: N₂O rapidly exits blood into alveolus on cessation, diluting O₂
• This is hypoxic hypoxia – give supplemental O₂ on emergence

So we’ve handled all the numbers that you need to know. But what about the utilisation of nitrous oxide in practical anaesthesia? Because I’m sure you’ve heard of a number of terms explaining interesting things that happen when you administer nitrous oxide.

Now, I can remember going into the exams really struggling to differentiate the concentration effect and the second gas effect and always getting them mixed up. And it took me until quite late to realise that you can’t have one really without the other. And whilst we consider these to be the case for nitrous oxide, any gas that has rapid uptake into the lungs can trigger these behaviours.

So what is the concentration effect? When you administer a high concentration of a carrier gas that is associated with rapid alveolar uptake, you will draw further gas down the airways into the alveolus. What’s really happening here? So we’ve got 50% nitrous oxide in the alveolus alongside some sevoflurane and some oxygen and a bit of nitrogen. That nitrous oxide wants to howl its way across that alveolar membrane into the blood. And it does so more rapidly than the volatile and the oxygen.

As you can imagine, if we were to close the top of that alveolus off, we would shrink the volume of the alveolus because almost 50% of it has been taken up by the blood and disappeared off. But we know that the lungs don’t randomly clamp off alveoli and that alveolus is in continual communication with the conducting airways. So if you rapidly hoover out, in our case, 50% of the volume, you will draw down more gas. Now that gas mix, remember, is going to be more nitrous oxide, more volatile, and more oxygen to refill that 50% space.

So the concentration effect involves the drawing down of extra gas from conducting airways into alveolus due to rapid uptake of that gas.

What is the second gas effect? This is caused by the concentration effect, noting that we’ve drawn more gas down into the alveolus, and at stage one of that we had 5% volatile, for example. But now, we had the original 5% volatile in the alveolus, and we’ve drawn down 50% of that alveolar volume that just so happens to have 5% of that 50% being volatile. I don’t want to cause confusion here.

So we’re going to think that our alveolus is 100 mls in size, and 50% of that was nitrous oxide in our phase one stage. And that 50% nitrous oxide has dumped into the blood, so we now have a 50 ml space. And we’re going to fill that 50 millilitre space with more conducting gas from the airways. That conducting gas, remember now, is going to be 50% nitrous oxide, but 5% volatile, plus some oxygen, plus a bit of nitrogen.

That means that now the amount of volatile in our alveolus has gone up. That means we’ve increased the concentration of volatile in the alveolus. That means that the gradient of volatile in alveolus to volatile in blood has increased. We all know that higher concentrations of sevoflurane administered to patients yields a more rapid onset of anaesthesia. That is the second gas effect.

So concentration effect involves drawing more volume into the alveolus. The second gas effect is a consequence of the concentration effect that leads to more volatile, in this case, being administered to the alveolus. I hope that explains it.

But what goes in must come out. And I’m sure you can now imagine that if we were to stop administering 50% nitrous to someone, we’ve removed that pressure to keep it in them. And it doesn’t want to be in people. It wants to be out. It wants to be free. So it starts dumping itself back into the alveolus.

At an alarmingly rapid rate, this washes out the alveolus. And you can imagine, well, that’s a good thing, because then if the alveolus, you know, doesn’t have the volatile in it because it’s been washed out by the nitrous trying to escape, then surely that’s going to increase the speed at which the volatile offsets. And you’d be right. But also, you’re washing out oxygen from the alveolus. If there’s no oxygen in your alveolus, then your red blood cells will potter past it and not pick up oxygen. And you’ll end up with a blue patient. And quite a rapidly blue patient. This is hypoxic hypoxia. Remember all those versions of hypoxia? You know, histotoxic, hypoxic, distributive, and another one. There’s a vivacast on that.

Diffusion into Air-Filled Spaces

[30:02–32:32]

Key points:

• N₂O is 34× more soluble than nitrogen, 16× more than oxygen
• Rapidly equilibrates into any air-filled space
• Compliant spaces (gut, lungs): Volume increases
• Non-compliant spaces: Pressure increases
• Clinical implications: Worsens pneumothorax, pneumocephalus
• Eye surgery: Can raise IOP with intraocular gas bubbles → blindness reported
• Long cases: N₂O enters ETT/LMA cuff → cuff pressure increases

Nitrous oxide, as we mentioned, is very very soluble. It’s 34 times more soluble than nitrogen, 16 times more soluble than oxygen. So if you have an airspace inside a human that’s currently, for argument’s sake, 21% oxygen, some nitrogen at 78% and a bit of CO₂, and you introduce nitrous oxide to that human as another fraction of gas within them, then the nitrous oxide is going to want to equilibrate out into that airspace. And if someone’s filled up with 50% nitrous oxide, then that airspace is going to want to have 50% nitrous oxide in it. It doesn’t mean that the other gases are going to get resorbed completely, and we’ll go a little bit further into that in a second.

But this leads to bad things. So if someone has a pneumothorax and you don’t notice it, and you’re trying to straighten out their broken leg, you make their pneumothorax worse. If someone has pneumocephalus for some inexplicable reason, you will make that space fill with more volume of gas. Bad.

Now if this is a nice stretchy space like a lung or your gut, then pressure doesn’t go up. But if this is a less stretchy space, then pressure rises instead. Remember the gas laws.

It has occurred in eye surgery. Sometimes in eye surgery, a gas is inserted into the intraocular space in the vitreous area to press the retina back down onto the posterior aspect of your eyeball. Give someone nitrous and you fill that gas space that has a particular type of gas in it up with nitrous too. That eyeball’s a somewhat fixed volume in a fixed orbit. Intraocular pressure goes up and perfusion of the retina goes down and people have been blinded.

Equally in long cases nitrous oxide can get into your endotracheal tube cuff or the cuff of your LMA. That cuff will stretch through.

Tank Properties and Entonox

[32:32–35:31]

Key points:

• N₂O tank pressure remains constant until liquid phase exhausted (must weigh tank)
• High flow causes cooling (latent heat of vaporisation)
• Entonox: 50:50 mix of N₂O and O₂
• Made by bubbling O₂ through N₂O
• Pseudo-critical temperature: -6 to -7°C (Poynting effect)
• Stored in white/blue checked shoulder cylinders at 137 bar
• Below pseudo-critical temp: Gases laminate
• If laminated: Initially delivers mostly O₂, then progressively hypoxic N₂O mixture

There’s a decent article on saturation diving and how they muck around with the amount of various gases inside a human. It is really interesting. Saturation diving in general is quite cool because these folks live at high pressure for yonks. Like weeks on end in tanks pressurised. Originally, they couldn’t communicate with the outside world because their speech, whilst audible to them in their high-pressure environment, would come out through a microphone all garbled. So someone had to write software to de-garble the sound that was being transmitted through a higher-density medium to a microphone to then come out of a speaker into a lower-density medium.

And now, getting well off track here, what is in your tank of nitrous? This is important to note because the pressure in that tank on that gauge will stay practically the same as you empty that tank because you’re constantly replenishing the gaseous phase with the liquid phase. Therefore, the pressure is going to remain somewhat constant. You won’t see a drop in pressure until all the liquid in that tank is converted to gas. Therefore, you don’t know how much is in that tank unless you weigh the nitrous oxide tank. So the pressure gauge is not of much use to you on a nitrous oxide tank until there’s not very much nitrous oxide left.

Now if you’re taking litres and litres and litres off, that tank is going to cool down courtesy of latent heat of vaporisation and therefore the availability of nitrous oxide in that tank might drop off slightly. You might see the pressure drop off ever so slightly. Once that tank warms up again, that pressure is going to normalise again.

Now this is very different to Entonox. Entonox being a 50-50 mix of nitrous oxide and oxygen that is used for analgesia, broken bones, maternity, etc. Entonox has some interesting properties. It is made by bubbling oxygen through nitrous oxide and somewhat dissolving the two together. So it doesn’t have a critical temperature, it has a pseudo-critical temperature of -6 to -7 degrees. This situation is described as the Poynting effect in that these two gases dissolved together have properties that would not be predicted by its constituent parts.

It comes in tanks with white and blue checked shoulders and it is at 137 bar. Below this pseudo-critical temperature, these gases laminate and that means that you end up initially delivering lots of oxygen and not very much nitrous oxide. And as you empty that tank, you then end up delivering more and more and more nitrous and less and less oxygen until you’re administering a hypoxic mixture.

Summary and Closing

[35:31–37:01]

Key points:

• Nitrous oxide supports combustion
• “Phlogisticated” relates to the phlogiston theory of combustion

Try not to use it because it is quite injurious to polar bears, but not as bad as desflurane. And just appreciate that once upon a time, it was called phlogisticated nitrous air. I don’t even know what phlogisticated means. Oh, phlogisticated. Ah, phlogisticated is associated with the phlogiston theory. As you might expect, a superseded scientific theory postulating that there was an existence of a fire-like element, dubbed phlogiston, within combustible bodies, that was released during combustion, a.k.a. nitrous oxide supports combustion, which we know and which you should definitely remember. There we go. Anyway, have a nice week. I hope you had a lovely Christmas and New Year’s.