It takes approximately fifteen seconds for Propofol to kick in and knock you out. That’s almost as fast as our immune system, as discussed in our previous article.

Yes, fifteen seconds of IV infusion of this drug and you go from a totally conscious state to deep coma. But Propofol is only one of the ingredients of the fascinating TIVA “cocktail”, and if you want to learn more about it, then sit back and enjoy this article!

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Once upon a time in the 1st century AD, a guy called Pedanius Dioscorides (known as the father of “Pharmacology”) discovered that the lovely plant called Mandragora had a narcotic effect on people (do not ask me how he discovered this; I have no idea). He was also one of the very first scientists to describe the effects of cannabis, but let’s keep this topic for our next article 👀

Nowadays, Anaesthesiologists only use Mandragora on valentine’s day as a gift for their sweethearts (imagine that!). People still use this plant in some folkloric celebrations and as a herbal remedy, but it is definitely not part of today’s mainstream anesthesia.

In modern times, prior a surgical intervention, the Anaesthetist must ensure that the patient will not feel any discomfort. After all, who wants to undergo a surgical procedure and experience the feeling of a cold scalpel on their skin? I yet have to meet such a person.

There are several different types of Anaesthesia. Some of them will only numb the skin locally (Local Anesthesia), others will cause the block of an entire region of the body (the so called regional anaesthesia or regional block, of which the spinal and epidural are part). However, there is one type of Anaesthesia that is capable of abolishing consciousness, pain, and muscle activity, and this is the TIVA – total intravenous anaesthesia.

The following triad characterised TIVA:

– Narcosis (or Hypnosis);
– Analgesia;
– Paralysis.

The name is self-explanatory, but I want to emphasize the obvious here, just for the sake of being a little pedantic: ONLY IV DRUGS are used in TIVA. No intramuscular, no pills, no sublingual. Only intravenous infusions and boluses.

Another big topic in anaeshtesia is INHALATION AGENTS, but we will not discuss it here (I strongly invite you to read about it tho).

Let’s break TIVA down

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Part 1 – Hypnosis

Hypnosis is extremely important for TIVA and it can be achieved with drugs called hypnotics. Hypnotics can be classified into two categories:

– Barbiturates (such as Thiopentone);
– Nonbarbiturates (Propofol, Etomidate, Ketamine, Opioids, Benzodiazepines, Ketamine, etc…).

Opioids and Benzodiazepins can also be classified as hypnotics, apart from being painkillers (opioids) or anxiolytics (benzodiazepins), and this is because, at higher doses, they can induce hypnosis and respiratory arrest. They are rarely used as hypnotics tho.

The role of hypnotics is to make patients uncounscious, to “induce” them into a state of coma. They put you asleep, thus helping the patient during the traumatic intraoperative time. But do not fall into the trap of thinking that, just because hypnotics put you asleep, they help with pain. In fact, the most used hypnotics (namely Thiopentone, Propofol, and Etomidate) DO NOT ABOLISH PAIN. One exception is Ketamine, which is also a very powerful analgesic. But generally hypnotics only deprive you of consciousness.

THIOPENTONE is the only barbiturates worth mentioning. This drug works just as fast as its non-barbiturate cousins and is metabolized by the liver. Reasons why anaesthetists would choose Thiopentone over Propofol are:

– rapid induction intubation (during emergencies);
– less cardiodepressive;
– less epileptogenic than Propofol.

Absolute contraindication for Thiopentone is Porphyria.
PROPOFOL is the master of hypnosis. Doctors mostly use it to put patients to sleep for surgery. It acts fast, is metabolized mostly by the liver and some by the kidneys, and works wonders (apart from some sexual fantasies and hallucinations as side effects, but we can live with that, I guess). Propofol injection is painful. Sometimes, a little bit of local anaesthetic will be necessary to numb the area before injecting it. Doctors can use it safely in pregnant women and children under three years of age; it has antiemetic and bronchodilating effects. It is a good drug, which serves its purpose perfectly. It is just very expensive.

ETOMIDATE is the drug of choice for cardiac patients. It is cardio-stable, but it can cause adrenocortical suppression, so doctors use it instead of Propofol only when needed.

Propofol, Etomidate, and Thiopentone share the same mechanism of action: they all potentiate the effect of GABA in the CNS, causing depression.

KETAMINE is the last hypnotic I will mention here. It is an NMDA inhibitor, and its peculiarity is something called “dissociative anesthesia,” which sends the individual into a cataleptic state.

Ketamine is unique because it acts on both brain cortex, causing inhibition and unconsciousness, and THALAMUS, causing analgesia. It is the only hypnotic to have excellent analgesic action.

Unfortunately, Ketamine increaes all the pressures (ICP, BP, Intragastric pressure, etc…) so making this drug not suitable for patients at high risk of aspiration or patients with increased ICP (intra-cranial pressure). Its main side effects are visual and (mostly) auditory hallucinations.

On the other hand, Ketamine is a potent bronchodilator, which makes it one of the drugs of choice for patients with active Asthma. Doctors can use it for patients in shock (⬆ BP), constrictive pericarditis, and cardiac tamponade (⬆ stroke volume), and for depressed patients (better post-surgical recovery).

This drug is a complete IV anaesthetic.

Part 2 – Analgesia

Pain is not good. And since hypnotics do not do much about it (apart from Ketamine), here it comes another group of drugs that can help with that: opioids.

There are a couple of good reasons why doctors prefer opioids like Fentanyl over other painkillers. Opioids act centrally and are very effective. Despite often being considered “dangerous” drugs, clinicians can manage them well. When used correctly, they have even fewer side effects than NSAIDs. Constipation and urinary retention, the main side effects of opioids, can be easily resolved post-operatively.

Opioids can also help reducing pulmunary oedema, which is a nice bonus!

We can devide opioids into:

– pure-agonists, like Morphine, Fentanyl, Alfentanyl and Remifentanyl;
– agonist-antagonists, like Buprenorphine;
– pure-antagonists, like Naloxone.

All opioids activate Mu, Kappa, and Delta receptors, generating pain relief. Doctors primarily administer Fentanyl, Alfentanyl, and Remifentanyl during TIVA, with Fentanyl being the most commonly used nowadays. They all come from morphine, so analgesia can develop into sedation and respiratory depression at higher doses.

Agonist-antagonists are interesting because they exhibit agonistic action only up to a certain dose, something called the “ceiling effect,” which makes them less prone to abuse and somehow “safer.”

In clinical practice, doctors use Codeine, Heroin, and Methadone less frequently or not at all (due to heroin’s high addiction potential and methadone’s primary use in opioid withdrawal syndrome).

Part 3 – Paralysis

Men from South America were probably the first to extract paralytic compounds from plants like the “Chondrdendron tormentosum” (can you repeat that aloud fast 3 times?). The name of this compound is “curare“. This herbal extract has the capability to interrupt the neuromuscular transmission, so causing muscle paralysis, which is very convenient if you are hunting. Curare is not used in modern anaesthesia.

Paralytic agents (also known as muscle relaxants) used in today’s anaeshtesia help facilitating intubation by relaxing muscles. These are devided into two categories:

– depolarising agents (Succinylcholine);
– nondepolarising agents, subdivided into Steroidal (Rocuronium, Vecuronium, Pancuronium) and Benzylisoquinoline (Atracurium, etc…).
The first difference between these two types of paralytic agents is their mechanism of action (MoA).

Depolarising agents (like Succinylcholine) bind to nicotinic (nAChRs) receptor on the muscular endplate of skeletal muscles, accumulating into the post-synaptic membrane. Initially, it has an “agonistic” effect, causing muscle fasciculations and mimicking ACh. Once in large quantities, succinylcholine (also known as Suxamethonium) keeps depolarising the membrane of skeletal muscles to the point of causing the same muscles to become refractory to stimulation. In other words, prolonged stimulation of muscle fibers by Suxamethonium makes them unresponsive (refractory) to further stimulation, so leading to flaccid paralysis. This phenomenon is called “phase II” block.

When using depolarizing agents, the main (and dangerous) possible complication is “malignant hyperthermia,” which causes the patient’s body temperature to increase by 1°C every five minutes and can be fatal.

Other side effects include anaphylaxis and masseter spasm, among others.

During emergencies, clinicians primarily use depolarising agents for rapid sequence intubation because of their rapid onset of action. However, their notorious side effects deter anaesthetists from using them routinely.

Nondepolarizing muscle relaxants (NDMR) are safer and their MoA simpler: they antagonise nAChRs causing flaccid paralysis. You can also easily reverse NDMR with drugs like Sugammadex (for steroidal) and Neostigmine (for benzylisoquinoline), making them safer for patients.

Clinicians prefer NDMRs over depolarizing agents, even though NDMRs have a slower onset.

Benzodiazepines as “pre-medication”

If asked what hypnotics and benzodiazepines have in common, the answer is: they both work on GABA receptors, causing CNS depression.

Doctors do not include benzodiazepines like Midazolam in TIVA, but they commonly use them as pre-medication for anxious patients (anxiolytic effect) and to elicit anterograde amnesia, which helps patients forget the trauma of surgery.

Note that Methohexital is identical to Thiopentone, with the difference that the former has an anticonvulsant effect whilst the latter is more epileptgenic. You can also ignore neuroleptanalgesia.

TIVA is a fascinating topic that deserves further exploration through additional research and readings. This article had the only purpose of offering you a framework from where to start understanding the foundations of total intravenous anaesthesia, and I hope that it managed to accomplish that!

Finally, I would like to recommend a good resource for your Anaesthesiology exam preparation:

Anesthesia secrets (Brian Keech, Ryan Laternza)
This textbook covers the essential syllabus needed to gain basic knowledge in Anesthesia. Highly recommended!

To the next article!