Introduction		Ether (diethyl ether)
How do volatile agents work?		Halothane ("Fluothane")
Solubility and Uptake		Trichloroethylene ("Trilene")
Volatility		The newer agents
Potency		How should volatile agents be used?
Pharmacological Effects		Further reading
What agents are available?

Introduction

One of the prominent features of anaesthetic practice in developing countries is the widespread use of volatile anaesthetic agents. This is surprising, as they are relatively expensive. Even modest supplies of halothane, for example, can cost several times more than the salary of the person using it but despite this burden on limited budgets, in most government hospitals cases are done using general anaesthesia with halothane and no other drug. However, many mission hospitals favour spinal anaesthesia for reasons of cost.

The demise of inhalation anaesthesia is sometimes predicted, partly because of cost and partly because of pollution of the atmosphere. Total intravenous anaesthesia may one day replace it. This event is probably far away and volatile agents will remain a central part of anaesthesia practice for many years to come.

An important safety feature of all volatile agents is that most of what goes into the patient via the lungs should come out the same way. Therefore the anaesthetic effect is reversible, as long as the patient is breathing. Also, with spontaneous breathing, the patient adjusts his or her own "dose " and respiratory depression will reduce the amount of vapour taken up and help prevent overdose. With controlled ventilation it is very easy to give an overdose.

A typical general anaesthetic (GA) using halothane or ether and nothing else is "bumpy", often unpleasant for the patient during induction and recovery, but reasonably safe.

The cost of some of the newer agents is very great and they are not generally used in developing countries. The cheaper, older agents, like ether, though widely used in poorer countries, are hardly ever used in the west. Most anaesthetists in the western world today have never given ether anaesthesia. 

How do volatile agents work?

An agent breathed into the lungs will dissolve first in the blood and then be carried to all parts of the body and dissolve in the tissues. The agent that dissolves in the brain produces the state of anaesthesia. The brain, being mostly fat, absorbs a lot of the agent. Many theories have been considered to explain how anaesthesia is produced. One suggests that the fat in the cell wall swells up. This reduces the ability of the nerves to conduct impulses to each other and activity is reduced, or stopped altogether if you give an overdose. Fortunately, the higher centres controlling consciousness are the first affected and the vital centres such as the respiratory and vasomotor centres are more resistant to this effect. Thus we take it almost for granted that the anaesthetised patient will go on breathing with a near-normal pulse and blood pressure.

There are four broad physical properties of any agent that will tell the anaesthetist how it behaves in and out of the body and, therefore, how to use it to best advantage. 

1. Solubility and Uptake.

The blood solubility of an agent is related to its blood-gas partition coefficient. The partition coefficient is a simple ratio of amounts: eg. the blood/gas coefficient is the ratio of the amount dissolved in blood to the amount in the same volume of gas in contact with that blood. The more blood-soluble the agent (high blood-gas partition coefficient), the slower the onset of effect and the slower the patient goes to sleep. Thus a very soluble agent eg. ether will dissolve in large quantities in blood before the brain levels can rise sufficiently to produce anaesthesia. To understand this concept, think of the circulating blood volume as a large pool, soaking up agent and not allowing the brain to have any.

An anaesthetic agent does not "target" the brain: it dissolves in all tissues according to the tissue/gas partition coefficient for the particular agent in a tissue type. The blood flow to that tissue and the mass of tissue present will also determine the amount of agent reaching it and accumulating there. Fat stores, like the brain, have a very high affinity for anaesthetic agents. Luckily for the induction of anaesthesia, body fat has a very poor blood flow and during a short or medium length operation, only a limited amount of agent will have dissolved there.

Similarly, a high cardiac output such as may be found in fever or fear will cause more agent to be dissolved in blood and tissues other than brain, thus delaying the onset of CNS effects. In all these instances, there is said to be a high uptake of the agent into the body, i.e. the venous blood returning to the heart has a low concentration of the agent and there is room for lots more. Paradoxically, though a high uptake means a lot of agent is disappearing into the body, blood levels rise slowly and the patient takes a long time to go to sleep by inhalation.

High uptake will also mean slow recovery because during the process of induction and maintenance, a large reservoir of the agent will have accumulated in blood, fat and other tissues like muscle. At the end of a long operation, this reservoir will slowly give up its stores of anaesthetic agent and thus act like a depot, delaying recovery. As ether is very blood soluble, it leaves the blood slowly and therefore circulates for a long time, before it is finally excreted out from the lungs. Blood levels fall slowly delaying a return to consciousness. Halothane, being fat soluble, also remains for hours in the fat of an obese patient at sub-anaesthetic levels, slowly being washed out long after the operation is over. But, the blood solubility is lower than ether and therefore blood levels fall more quickly. Thus the level in the brain falls more quickly, as the blood is able to "wash" the agent out. The patient therefore recovers consciousness more quickly than when ether has been used. Tissue blood flow and cardiac output are important determinants in the elimination of highly soluble agents.

The opposite happens in shock, with a low cardiac output: in this case blood levels rise quickly, induction is fast and uptake is low.

It can now be understood what happens when an agent with a very low blood solubility is used (low blood/gas partition coefficient). Blood levels rise very rapidly, leading to a rapid induction of anaesthesia. When the agent is stopped the reverse happens: blood levels fall very quickly and recovery occurs after a short interval, no matter how long the agent has been used. Changes in cardiac output have little effect on the speed of induction of anaesthesia. The gas, nitrous oxide and newer agents, sevoflurane and desflurane are examples of very insoluble drugs. 

2. Volatility.

An agent with a low boiling point will evaporate easily and therefore be more available than one that has a high boiling point. Ether is highly volatile and thus there is almost no limit to the concentration that a vaporiser can give. Ether is really too volatile to be convenient and sometimes new, sealed bottles arrive with no agent inside, but at least it means we can give plenty of it to counteract its slow onset. Trichloroethylene, on the other hand, only reluctantly becomes a vapour and we have difficulty in getting it into the patient in sufficient quantities. Halothane is in between and has a near-perfect profile of physical properties.

Another index of volatility is the Saturated Vapour Pressure or SVP. It indicates the maximum proportion of atmospheric pressure which can be occupied by the vapour of an agent. Ether has an SVP of 425 mmHg and theoretically will allow a maximum concentration of 56% (425/760 x 100). SVP is dependant only on the temperature and not on atmospheric pressure. 

3. Potency.

Regardless of solubility and boiling point, each agent will have its own potency value. This is called the MAC - the Minimum Alveolar Concentration. This is the concentration at equilibrium required to prevent a reflex response to a skin incision in 50% of patients. Thus the potency of different agents can be compared by showing how much you need to produce the effect you want, expressed as a percentage vapour strength.

An agent with a low MAC, is a potent agent because only a small amount is required to produce anaesthesia. A high MAC means the agent is weak because a lot of agent is required to produce anaesthesia. Ether has a high MAC, is a weak agent, while trichloroethylene has a very low MAC, is potent and produces its effects at a fraction of the concentration of that needed for ether. Once again, halothane has the ideal MAC, somewhere in between. If the agent is being used alone with spontaneous breathing in a fit patient, you will need to set your vaporiser to at least three times the MAC to keep the average patient settled during surgery.

The MAC of any agent is broadly determined by its fat solubility: the more fat soluble, the greater the potency. 

4. Pharmacological effects.

Although we say that ether is weak, it is difficult to believe this statement if you see a patient totally unrousable after ether anaesthesia, a common occurrence. To explain this, one has to think of the different ways an agent works: the anaesthetic effect, the analgesic effect. the volatility and correlate these with the properties outlined above. Ether is very volatile, has good anaesthetic and analgesic effects and these, with the large reservoir effect and slow recovery, make it an effective anaesthetic, despite its low potency.

Halothane is a good anaesthetic, but a poor analgesic. Thus the combination of low solubility, a small blood reservoir and postoperative pain causes the patient to wake up quickly.

Trichloroethylene is a good analgesic but the patient breathing this alone will never get to the state of anaesthesia at all unless he is given the agent for several hours because it does not evaporate enough to give a sufficient inspiratory concentration and is rather blood soluble.

The side effects of the individual agents are mentioned in more detail below. All volatile agents trigger Malignant Hyperthermia. 

(Continued ...)

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