Thiopentone Introduction

Currently considered to have the fastest on set(1 arm brain circulation for a pre-calculated induction dose) out of the commonly used induction agents (propofol, ketamine, etomidate)

When paired with suxamethonium you have the quintessential RSI cocktail. A paucity of opiate here is the drawback, but it does work proper quick, just don’t look at the blood pressure during laryngoscopy.

Thiopentone is a barbiturate,  particularly, a sulphur analogue of phenobarbitone,  It doesn’t mix very well with other drugs, so some good flushing action between syringes doesn’t go amiss. (Most muscle relaxants bar (the least being mivacurium), causes thiopentone to precipitate)

It is the most lipid soluble of the common barbiturate agents

It does hang around, and does result in people taking time to wake up… especially the elderly, especially if you take them back to theatre because their appendix tie has fallen off and they have poo coming out their drain and you use Thiopentone again!

Model Answer and Questions

Doctor, in a structured manner take me through Thiopentone

Overview

• Thiopentone is a barbiturate classed induction agent.
• Presented as a yellow powder, stored in a nitrogen atmosphere with additional sodium bicarbonate. Ampoules contain 500mg.
• Prepared with water for injections, it has a pH of 10.5.
• It is very stable once prepared and bacteriostatic at such an alkaline pH.

Mechanism

• Its chief mode of action is at the GABA receptor, increasing the period of time they are open.

Use

• Its chief use is the induction of general anaesthesia and is used as an agent for refractory seizure disorders where it may be used in infusion.
• It is also used in situations where achieving the lowest cerebral O₂ demand may carry clinical benefit.
• Infusions are also used to control raised intracranial pressure.

Contraindicated in

• Porphyric patients.
• Myasthenics and those with familial periodic paralysis.

Dose

• 2-7mg/kg providing 5-15 minutes of general anaesthesia.

Pharmacokinetics of Thiopentone

Absorption

• Routes include IV, oral, and rectal (1 gram / 22kg bodyweight, 15-minute onset).

Distribution

• 65-85% protein bound - chiefly albumin, also sequestered by RBCs.
• The rapidity of onset is facilitated by its high lipophilicity.
• pKa 7.6 - 60% unionised.
• VOD 1.9L/kg.
• It has the property of tautomerism. On injection into the blood, the pH drop causes the molecule to unionise into the thiol group and then to rapidly shift to pharmacologically active thiopentone.
• (ENOL) In the syringe, it is mostly ionised and more water-soluble in this form.
• (KETO) Once in the patient, the pH drops, it unionises, and then drops the hydrogen from its sulphur molecule, leading to a conformational change and much-improved lipid solubility.

Metabolised

• By the liver – oxidation, slow process, and readily saturated with infusion leading to a zero-order kinetic situation.
• 3-10% is broken down into pentobarbitone, which has a 1-3 hour plasma half-life (thiopentone 0-5 hours), the rest into non-active metabolites.
• It is a powerful enzyme inducer.

Elimination

• Plasma redistribution half-life of around 8 minutes.
• Removal from body half-life of HL 3.3-22 hours.
• Clearance of 2.7-4.1ml/kg/min.
• Given its propensity for zero-order kinetics and lipophilic nature, in an infusion, it will accumulate, leading to extended context-sensitive half-times.

Side Effects of Thiopentone

Cardiovascular (CVS)

• Dose-dependent reduction in cardiac output, stroke volume (SV), and systemic vascular resistance (SVR), worse in hypovolaemic acidotic patients.
• Less of a BP drop compared to Propofol.
• Venodilates.
• Dose-related myocardial depression – worsened in hypovolaemia.

Respiratory (RS)

• Respiratory depressant – Apnoea as it takes effect.
• Rare disposition to laryngospasm, increased airway reflexivity, and bronchospasm.

CNS

• Smooth, rapid induction of anaesthesia.
• Decreases cerebral blood flow (CBF), intracranial pressure (ICP), and intraocular pressure (IOP).
• Anticonvulsant.
• Reduces cerebral metabolic rate of oxygen (CMRo₂).

Gastrointestinal (GI)

• Depressed GI activity.
• Splanchnic vasoconstriction.

Renal

• Decreased renal plasma flow, increased ADH secretion (drop in urine output).

Gynaecological

• Crosses placenta.

Toxicity (TOX)

• Anaphylactoid reaction in 1:20,000.
• Extravasation may cause tissue necrosis.
• Arterial injection may cause spasm, thrombosis, and limb ischaemia – beware of the brachial artery!
• Prolonged/high-dose infusions may have an immunosuppressive effect.
• Can trigger porphyric crisis (along with etomidate, enflurane/halothane, lidocaine, clonidine, ranitidine, diclofenac, metoclopramide). Bupivacaine is safe.

Define or Die

Zero Order Kinetics

A situation where the reduction of a drug in a system follows a fixed rate of reduction per unit time. Think, 10mg cleared an hour every hour.

Example: Alcohol – one unit takes one hour to clear in a standard human.

The reason for this is chiefly the availability of enzymes. Thinking back to hepatic clearance: if you’ve only got '10 enzymes' and they are all active, then the rate of activity becomes fixed.

If you added 10 more, the rate would double.

This occurs if enzymes are particularly slow, or if there is an absence of them.

Conceptually, if an enzyme system is saturated and at maximum rate, and you keep adding substrate, then the patient will fill with substrate until you stop, and the substrate gets cleared.

You can imagine that as you get to a point where enzymes are not saturated anymore, then things speed up.

Most enzyme systems would eventually get saturated and shift from a first-order, rapid-clearance situation where there are a million enzymes to a few drug molecules, to a zero-order linear process.

This will be outlined in greater detail in the Michaelis–Menten episode, where we will talk formulas and graphs.

The contrary to this is the plasma esterase system, which is incredibly efficient, matched only by the blistering effectiveness of carbonic anhydrase in the red blood cell.

Bound Fractions

Its convenient chemical characteristics: its pKa is 7.6 – so at physiological pH it's 60% unionized. Bear in mind that only the fraction that is not protein-bound is influenced here, so out of your 500mg dose of thio, 12% is unionized and active.

• Noting that in an acidotic patient, or one with less protein, they will have a larger free unionized fraction, leading to greater potency. Other drugs that tend toward protein binding may also displace thiopentone into its freer form.

Tautomerism

Barbiturates are not readily soluble in water at human pH. Solubility depends on transformation from Enol to Ketol form, which is leveraged by having the bottle of Thio when mixed with water have a pH of 10.5 courtesy of the bicarb! –> Tautomerism.

A type of structural isomer (a molecule that has the same atoms in a different layout) where a change of structure is brought about by a change in environment. Another molecule that does this, which we care about, is midazolam.

Application Clinically

Induction agent for: RSI + refractory status epilepticus.

Less used these days, but some obstetric GA is conducted with thio due to its onset time and stability. (don'tmix up syringes with the cefuroxime tho)

My first RSI was with alfentanil, thio, and sux, with a good flush between them all. There is definitely a rapidity to it, but there are drawbacks, such as deteriorating intubating conditions over time with suxamethonium and possibly a greater risk of patient awareness.

Not as quick to draw up as an amp of propofol either.

I would be tempted to use it chiefly in a refractory status patient or in a situation where, despite a general anaesthetic, the patient is still seizing when the paralysis wears off (a generally bad news situation).

Summary

Thiopentone was once used quite a lot but is no good for laryngeal masks / supraglottic airway devices.

The story of soldiers after Pearl Harbor: rumors had it that lots of soldiers fared poorly having emergency anaesthetics for injuries sustained. There appear to have been a few excess deaths, perhaps 5–10, due to heavy-handed barbiturate dosing leading to circulatory collapse. It later came about that concentrations of perhaps a quarter of those, administered in small aliquots over time, might be a smarter move in those who are sick. One case involved using 400mg of thiopentone over 1.5 hours with a nitrous oxygen mix for a shocked patient (GSW). Three weeks later, the patient handled 400mg in 10 minutes.

References

• Bennetts FE. Thiopentone anaesthesia at Pearl Harbor. Br J Anaesth. 1995 Sep;75(3):366-8. doi: 10.1093/bja/75.3.366. PMID: 7547061.

---

"Thanks for listening guys... Every day you are getting better at this. Take it day by day, don't overcook yourself, don't freak out, and keep studying!"

Podcast Information

Transcript Thiopentone For The FRCA Primary

Introduction and Podcast Overview

00:00-00:37

Please listen carefully. Hello, and welcome to Gas, Gas, Gas, your one-stop podcast for the FRCA primary exam. This podcast will fill your brain with information. Listen to it, think about it, and check out the show notes on the website. There, you will find the core diagrams you need to be able to draw and describe for the exam. This podcast can squeeze into your day - listen while you're driving to work, cooking dinner, maybe when you're on call, or in the gym. Eventually, the revision is going to end, but for now, expect facts, concepts, model answers, and the odd tangent. Remember to rate and follow the show to hear much, much, much more.

Topic Introduction: Thiopentone Overview

00:37-02:32

Hello, everyone. This is James at Gas Gas Gas. Today we're talking thiopentone. Thiopentone - thio - is a classic induction agent but is perhaps less commonly used nowadays compared to its historic use. It still probably has a niche, and it's something you're going to need to know about for the exams.

Some general notes. It's considered to have the fastest onset time of all the induction agents that you might come across, described as inducing anaesthesia in one arm-brain circulation time for a precalculated induction dose, which is quicker than propofol, ketamine, and definitely quicker than etomidate, which seems to take forever.

Classically, when paired with suxamethonium, you have the quintessential RSI cocktail. This is the classic RSI described as opposed to the modified RSIs that I'm sure you've seen and you've conducted yourselves, with a multitude of other agents in a multitude of other manners delivered.

With this RSI cocktail, one of the drawbacks is the paucity of opiate described. So whilst it works real quick, don't look at the blood pressure during laryngoscopy 'cause it's going to be high. Not ideal for a number of patients.

Drug Characteristics and Compatibility:

Thio itself is a barbiturate, particularly it's a sulphur analogue of phenobarbitone, another barbiturate. Important things to note: it doesn't mix very well with other drugs, so some serious flushing action between syringes is required. It is definitely not friends with most muscle relaxants. By that I mean atracurium, rocuronium, suxamethonium - the only one it might behave slightly well with is mivacurium, that very commonly used paralysing agent. Thio mixed with any of these leads to precipitation. You might block your cannula and you're going to feel pretty stupid about it, especially if you're halfway through an anaesthetic and you can't finish.

It is the most lipid soluble of all the barbiturate agents as well. It has a tendency to hang around, especially in elderly patients, and especially if you've given more than one dose of it.

Complete Model Answer: Thiopentone

02:48-06:11

So, with no further ado, Doctor, in a sensible manner, talk me through thiopentone.

Ah, so thiopentone is a barbiturate class induction agent. It is presented as a yellow powder stored in a nitrogen atmosphere with the addition of sodium bicarbonate. It's generally issued in ampoules containing five hundred milligrams. This is prepared with water for injections, generally with twenty mils, yielding a twenty-five milligrams per mil, 2.5% concentration syringe. It has a pH of 10.5, very alkaline, and it's quite stable once prepared, and is considered bacteriostatic at such an alkaline pH.

Mechanism and Indications:

Its mechanism is chiefly at the GABA receptor, increasing the period of time they're open, and it's generally used for induction of general anaesthesia, managing refractory seizure disorders, and as an adjunct to reducing intracranial pressure in those with raised intracranial pressure, i.e., the head injured.

Its chief contraindication is in patients with porphyria, where it can precipitate a porphyric crisis. Generally, bad news for them.

Dosing and Routes:

Its dose is 2 to 7 milligrams per kilo and it gives you about 5 to 15 minutes of general anaesthesia. As an aside here, guys, you've got to think about how much alcohol and other drugs your patient might consume. If they're quite the boozer and they've not had booze in a while, much like with other anaesthetic agents, they're gonna wake up quicker because their neurons are inherently more jazzed up at baseline.

Routes of administration include intravenous, oral with a significantly prolonged onset time, and rectal. The dose for a rectal induction of anaesthesia would be one gram per twenty-two kilos of body weight, taking about fifteen minutes to work.

Pharmacokinetics:

Distribution wise, it is considered sixty-five to eighty-five percent protein bound - we'll just describe it as eighty percent protein bound, mostly to albumin. Its pKa is 7.6, so the free fraction is sixty percent unionised, and its volume of distribution is 1.9 litres per kilo.

Of note, it has the property of tautomerism. So on injection into the blood, the pH change from that quite alkaline pH of the syringe to a more physiological pH leads to the molecule going from more water soluble to less water soluble and less lipid soluble to more lipid soluble in the plasma, as it unionises and undergoes this tautomeric shift into the pharmacologically active thiopentone. More on this later.

Metabolism:

It's metabolised by the liver, undergoing an oxidation reaction, which is reasonably slow and is readily saturated, particularly with infusions of thiopentone or multiple doses of thiopentone. Of note, 3 to 10% of thiopentone is broken down into pentobarbitone, which is another active metabolite, leading to prolonged sedation in perhaps the more elderly population. Also of note from the liver perspective, it's a powerful inducer of enzymes.

The plasma redistribution half-life is around eight minutes, and the clearance half-life is three to twenty-two hours or so. The body achieves 2.7 to 4.1 mils per kilo per minute clearance. So not bad, not great.

If you think about all these features, guys - the zero order kinetics, the high lipophilicity, the perhaps slow real clearance out of the body - you can make an assumption that the context sensitive half-time of this drug is going to be quite long if you happen to infuse it.

Clinical Applications and Infusion Use

06:28-06:56

Of note, infusing thiopentone is quite a rare event, reserved mostly on intensive care units for refractory status epilepticus, where you just need to turn the brain off for a period of time and hope that all those glutamic excitotoxic molecules calm down and then everything settles, or if someone's got rip roaring intracranial pressure as a last ditch attempt to lower it.

Comprehensive Side Effects Profile

06:56-09:20

Anyway, back to telling you all about thio. Side effects. So there's a range of side effects with thiopentone.

Cardiovascular side effects: There's a dose-dependent reduction in cardiac output, stroke volume, and systemic vascular resistance. You can also consider that this might be exacerbated in hypovolaemic patients and acidotic patients due to the increased fraction of available thiopentone. On paper, it probably yields less of a blood pressure drop versus propofol at similar anaesthetic doses, and it's noted to be a venodilator as well.

Respiratory effects: It is a respiratory depressant, and actually, on that initial dose of induction thiopentone, you might render the patient apnoeic. Contrary to that, though, the odds are that you've increased the reflexivity of the larynx and airways. So trying to site an iGel as an emergency in a thio-sux RSI when you can't intubate, you might find yourself struggling as that sux wears off and their upper airways are quite ticklish. Less of a problem if you're using rocuronium though.

CNS effects: So naturally, it's a smooth and rapid inducer of anaesthesia. It is an anticonvulsant. Its other useful features are that cerebral blood flow, intracranial pressure, and intraocular pressure - your eyeball pressure - all decrease, and it leads to a reduction in the metabolic requirements for oxygen of those neurons. If you're in a marginal state where you don't think you're getting much oxygen to many neurons due to bleeding, head trauma, injury, etc., you could reach for the thiopentone to reduce the oxygen demand. Other induction agents also have this effect, except for maybe ketamine, depending on who you ask.

Renal effects: The other chief relevant side effect is the influence it has on your urine output. So you get decreased renal plasma flow, perhaps secondary to the cardiovascular effects, but also an increased secretion of antidiuretic hormone, leading to the body being more driven to hold on to free water in the collecting ducts of your kidneys.

Obstetric considerations: Of note for obstetric anaesthesia is it does cross the placenta, so you might end up with an anaesthetised baby as it comes out. Some units still have thiopentone drawn up as the emergency agent of choice. That prescriptive nature is shifting away, and propofol is also a recognised option in this patient cohort. I suppose the advantage of the thio being left on the side all day is that it's bacteriostatic and actually lasts for quite a long time once drawn up and is very stable, whereas having a twenty mil syringe of propofol drawn up, sat on side all day, might raise a few eyebrows.

Toxicity and Safety Considerations

09:36-10:20

Toxic considerations: One in twenty thousand chance of an anaphylactic/anaphylactoid reaction. If you cause a large quantity of it to extravasate because you're using a dodgy cannula, you're probably going to cause tissue necrosis. And if you accidentally put it in someone's artery, you're going to trigger spasm and thrombosis, and limb ischaemia because it's going to precipitate once it gets to the capillaries and the pH shifts.

So beware desperate cannulas sited in ACFs in A&E, especially if you're reaching for the thio. If you've got a patient who's just seizing away, tricky.

Pharmacological Concepts: Zero Order Kinetics

10:20-12:45

Right, so we mentioned a couple of concepts there, and we're going to pick out a couple of them just to go over in a bit more detail. I've mentioned zero order kinetics. This describes an enzyme related clearance situation whereby you find yourself with a fixed clearance rate of drug per unit time. Think ten milligrams cleared an hour every hour.

A good example of this is actually alcohol, and that's why you think about alcohol in units. A unit of alcohol takes one hour for a standard human to clear because the enzymes involved in clearing alcohol get rapidly saturated. You can therefore imagine that if you were to have many, many doses of a drug that rapidly saturates an enzyme clearance system, it'll hang around for a really long time.

Thinking about zero order kinetics in another layer of detail, just think about this system as a product, substrate, enzyme situation and compare it with a graph in your mind of what first order kinetics looks like. First order kinetics would be where you have a situation with untold quantities of enzyme, all pretty keen to get going.

It is important to note that enzymes have different rates of activity. So you could have ten thousand very busy enzymes or ten thousand pretty lazy enzymes. You can imagine that the lazy enzyme situation is going to saturate more quickly if you provide it too much product. But below that saturation point, the curve of clearance is nonlinear and is actually probably a bit more logarithmic looking. We'll go into more detail on this when we do Michaelis-Menten kinetics. There's the nuance of not just the quantity of enzyme, but how speedy that enzyme is.

To tie this in, if you have an enzyme system readily saturatable, your drug infusion or drug dosing situation might be more susceptible to prolonged context sensitive half times. We mentioned this situation with fentanyl, whereby it's so lipophilic that eventually you fill the patient, much like you eventually fill the patient with sevoflurane.

Examples of enzyme systems that are very, very tricky to saturate would be the plasma esterase system, which is blisteringly fast and quite good at clearing remifentanil. This is reliant on the potency of remifentanil as well. If you imagined that remifentanil might be one-tenth as potent and you have to use more drug than we classically use, it could end up with a situation where we were to saturate the enzyme system.

Another example of a very efficient enzyme system that isn't terribly drug related is carbonic anhydrase activity in the red blood cell. And this is probably one of the fastest enzyme systems in the body, doing a very, very particular task of converting your CO₂ + H₂O ⇌ H₂CO₃ situation to carbonic acid and back in order to screw away carbon dioxide in your red blood cells.

Pharmacological Concepts: Protein Binding and Free Fractions

13:23-14:47

The next concept I've alluded to is bound fractions. So we've noted that thiopentone is eighty percent protein bound and is sixty percent unionised at physiological pH because of its pKa of 7.6. It's important to note, though, that the unbound active fraction is the part of it, the component of that dose that isn't bound to the protein.

So if you give one hundred milligrams, you know eighty percent of it ends up protein bound, then you're working with twenty milligrams of free drug, and so actually you've only got sixty percent of that twenty milligrams floating around being active. That relatively small fraction yields anaesthesia in one arm-brain circulation.

Therefore, it would lead you to think that a patient who was terribly acidotic or actually had nephrotic syndrome and didn't have very much protein in their plasma - you gave them the standard induction dose of thiopentone, and you'd probably end up in tiger territory with loads of unbound drug causing untold havoc on your cardiovascular system.

I think thio is a great way to illustrate that risk, and it's something to think about with other induction agents as well, considering their protein bound availability and what may or may not displace them. For thio, ibuprofen can displace it from albumin.

Pharmacological Concepts: Tautomerism

14:47-16:04

The last thing to mention here for thio is tautomerism - T-A-U-T-O-M-E-R-I-S-M. And this is a type of structural isomerism. You need to go read about isomers, and we're going to talk about them at some point.

What occurs in this situation is when it is made up with your water for injections in your syringe, it's quite an alkaline environment, and that environment influences the sodium thiopentone to remain in its keto form. It's nice and water soluble, which is what you want.

However, once you put it inside the patient, the pH drops naturally to physiological pH, and it unionises. It then subsequently drops the hydrogen from its sulphur molecule, leading to a conformational change in the thio that makes it much more lipid soluble. If this was the case in your syringe, then it would be quite hard to mix and draw up and deliver, wouldn't it? Because there's not much lipid in water and you'd have to try and mix it with, I don't know, soybean oil or something. I'm sure they don't.

So that's why you need to think about this. The other molecule in anaesthesia that we often tout as being tautomeric is midazolam, and we'll talk about that in a future podcast.

Contemporary Clinical Use

16:04-17:00

So when is thio actually really used clinically? From an educational perspective, the first RSI I did was with alfentanil, thio and sux, so it was a modified RSI. It works very quickly, but it is a bit of a faff to draw up if you've not paralysed your patient because you've tested if you can ventilate them before you do - another modified RSI technique. And you think, "Oh, I can't, what are you going to do? Are you going to paralyse them then when you've already been a bit cagey? Or are you going to stick an iGel in?" Patient probably won't tolerate the iGel very well because it's thio and you've not used propofol.

I would generally be tempted to use it in an adult with refractory status, although more commonly I would just reach for propofol, and perhaps think about thiopentone on ITU later when that paralysis wears off and actually the patient's still seizing away. If that's the case, despite your propofol infusion, then it's probably quite bad news for that patient.

Historical Context: Pearl Harbor

17:00-18:44

A historical note with thiopentone, and people might bring this up when they're talking about thio, is the story of soldiers in Pearl Harbor. Rumours exist that actually there was quite heavy-handed use of thiopentone and people weren't waking up afterwards and they presumed they were brain injured, brain dead, and they'd turn them off.

Looking at a few articles and some analysis of what was published after the war, because clearly during a war you're not going to publish to your people how many people were truly killed when an attack happens because it looks bad, it probably transpires that there were some unexpected deaths due to thiopentone, but that they were using either 5% or 10% concentrations of thio, and giving quite a lot, describing a situation where they would administer the drug and then describe a situation where the patient turned very mottled and died.

Later, in another letter or article to the editor, a physician describes using four hundred milligrams of thiopentone over one and a half hours whilst also administering nitrous and oxygen for a severely shocked patient who'd had a gunshot wound, administering 2.5% thiopentone in small doses. And that's like an induction dose of anaesthesia in an adult - four hundred milligrams over one and a half hours. Nitrous is good, but it's not sparkling.

But then close of the article by saying three weeks later when the patient needed a trip back to the theatre for some other sorting out, the patient chewed through four hundred milligrams of thiopentone in ten minutes. This really probably demonstrates that the fact that this bloke was probably very acidotic perioperatively, had quite a good free fraction of thio, and that maybe there was some enzyme induction that had happened for that second case. Who knows?

Conclusion and Call to Action

18:44-19:16

Anyway, getting carried away talking about thiopentone - it's a good drug, but there are better drugs now. If you found it useful or awful, please like and subscribe and rate the show. Definitely check out the show notes for those diagrams and the detail of this content. It is a bucket of content to get to grips with. Keep working at it and you will get better faster and stronger. It is vital to keep your interest alive for the science that we're covering and not overcook yourself. You will be amazed by what you know come exam day. Don't freak out, keep studying.