2.7: Inhalation Anaethetic Agents

Inhalational anaesthesia forms the basis of most general anaesthetic. In Western countries where ultra-short acting intravenous anaesthetic drugs and computer delivery systems are available, some anesthetists favor total intravenous anaesthesia (TIVA).

Inhalational anaesthetic agents include nitrous oxide and the volatile agents such as ether, chloroform, halothane, isoflurane, enflurane, methoxyflurane, sevoflurane, desflurane, cyclopropane and trichloroethylene (trilene). All the current agents may trigger malignant hyperthermia.

There are two methods to deliver volatile anaesthetic drugs: draw over and continuous flow. In a draw over system the carrier gases (air or air enriched with oxygen) is drawn though a low resistance Vaporizer by the patient’s inspiratory effort (or manual ventilation with a self-inflating bag). The draw over apparatus is robust, compact, portable, cheap and not dependent on compressed gases. During anaesthesia with continuous flow compressed gases at high- pressure pass though regulators that reduce the gas pressure, flow meters and then though a Vaporizer. Continuous flow apparatus is dependent on a supply of compressed gas. If the supply of compressed gas fails, the anaesthetic fails.

Anaesthesia can be induced intravenously and maintained with a volatile anaesthetic agent or volatile anaesthetic agent can be used for both induction and maintenance of anaesthesia.

The patient can breathe spontaneously or may be paralyzed with muscle relaxants. When muscle relaxants are used, the concentration of volatile anaesthetic agents should be reduced.Spontaneous ventilation with a volatile anaesthetic agent has greater safety. The patient will adjust his or her own dose. If the anaesthetic is “light” the patient will increase their respiratory rate and deepen their anaesthetic. If the anaesthetic is “heavy”, respiratory depression will occur and the patient will inhale less anaesthetic.

Inhalational induction of anaesthesia may be a good option for patients who may be difficult to intubate.

Ether, which is both an anaesthetic and analgesic, may be used as the only anaesthetic drug or combined with other drugs. Halothane and similar volatile anesthetics are not analgesics.

Pharmacokinetics

An inhaled anaesthetic agent will first enter the lungs, then the blood. The circulation will carry the agent to all the organs of the body including the brain. It is the partial pressure of the anaesthetic agent in the brain that will cause anaesthesia. There are many factors that determine the speed of onset of an inhaled anaesthetic agent including the inspired concentration, alveolar ventilation, solubility, and cardiac output.

The higher the inspired concentration of the agent the more rapid the rise in the partial pressure in the brain. Agents with a low boiling point will evaporate easily (are more volatile) and therefore can be delivered in higher concentrations. Ether has a boiling point of 35 degrees Celsius and could produce a maximum concentration of 56%.Trichloroethylene has a boiling point of 87 degrees Celsius and could only be given at a maximum concentration of 8%. Another way of expressing volatility is the saturated vapour pressure (SVP). The SVP is the pressure exerted by the vapor phase of an agent when in equilibrium with the liquid phase. The SVP of ether is 425 mmHg (59 kPa). The SVP of halothane is 243 mmHg (32 kPa). The SVP of trichloroethylene is 60 mmHg (8 kPa).

The higher the alveolar ventilation, the more inhaled anaesthetic agent will be taken into the lungs and the quicker the rise in the partial pressure of the agent in the brain.

The greater the solubility of the gas in the blood, the slower the rise in the partial pressure of the agent in the brain and therefore the slower the onset of anaesthesia. Avery soluble agent such as ether will dissolve in large quantities in blood before the brain levels rise enough to cause anaesthesia. More soluble agents will also have longer recovery. The solubility of an agent is called its blood-gas partition coefficient. 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. Ether is very soluble and has a blood gas coefficient of 12. Halothane with a blood gas coefficient of 2.3 has a much more rapid onset of anaesthesia. Trichloroethylene has high solubility with a blood gas coefficient of 9.

A high cardiac output will cause more agent to dissolve in the blood and organs other than the brain, thus delaying the onset of anaesthesia. Inhalation agents also vary in their potency. The minimum alveolar concentration( MAC ) is used to express the potency of inhalation agents. The MAC is the minimum alveolar concentration of an agent required to prevent a response to a skin incision in 50% of patients. The lower the MAC the more potent the agent. The MAC of an agen may be reduced (potency increased) by many factors including combining other central nervous system depressants, hypothermia, severe hypotension and extremes of age. The MAC of an agent can be increased (potency reduced) by factors such as hyperthermia,hyperthyroidism and alcoholism. Trichloroethylene has high potency (MAC 0.17%),halothane has a lower potency (MAC 0.75%) and ether has an even lower potency(MAC 1.92%).

The anesthetist can predict the behaviour of a volatile anaesthetic agent by the SVP, blood gas coefficient and MAC. Ether is highly soluble (Blood-gas coefficient 12) and will have a slow onset. With a MAC of 1.92% it has low potency but fortunately has an SVP of 425 mmHg, which means that it can be given in high concentrations.Trichloroethylene is potent (MAC 0.17%) but is a weak anaesthetic because Vaporizers cannot produce high enough concentrations because the volatility is very low (SVP 60 mmHg). It has a high blood solubility (blood-gas coefficient 9) so has a slow onset.Halothane is volatile (SVP 243 mmHg) so adequate concentrations can be delivered by a vaporizer. The solubility is low (blood gas coefficient 2.3), allowing rapid induction and recovery.

The effect of volatile anaesthetic agents on other organs is usually similar, however,there are some important differences.

Diethyl ether (Ether)

Ether is an inexpensive, colorless agent made from sugar cane with a strong irritant smell. It was used in the “first anaesthetic” (W.T.G. Morton, Boston, 16 October 1846).Ether has some significant advantages. It is both an anaesthetic and analgesic. Unlike other volatile agents, ether stimulates cardiac output (maintaining blood pressure) and respiration. (Ether is safe to use for spontaneous respiration without additional oxygen for most patients and is an excellent inhalation agent where oxygen is unavailable). Very high concentrations of ether may cause direct myocardial depression. Ether does not relax the uterus like halothane and some other volatile agents but gives good abdominal muscle relaxation. It is a good bronchodilator. 10 to 15% is metabolized. It should be stored in a cool dark place.

Though ether can be used a sole anaesthetic agent, as it is both an anaesthetic and analgesic, it has several properties that make it less than ideal. Inhalational induction by ether is very difficult because it has an unpleasant smell, is very slow, causes marked secretions (requiring atropine premedication), bronchial irritation, breath holding and coughing. Ether may cause postoperative nausea and vomiting (PONV) and recovery is slow. It is also flammable in air and explosive in oxygen and nitrous oxide.

Intravenous induction or using halothane for induction and then changing over to ether may overcome problems with ether inhalational induction. For intravenous induction the patient should be premedicated with atropine, pre-oxygenated, induced with thiopentone and intubated after receiving a muscle relaxant. Ether in air is delivered by intermittent positive pressure ventilation (IPPV) at 10 to 15% for about 2 to 8 minutes, then reduced to 4 to 8% depending on the patient’s need (sick patients may only require 2%). Patients who are spontaneously breathing after suxamethonium will require a higher maintenance concentration of ether (6 to 8%). Stop the ether well before the end of the operation to avoid prolonged recovery.

Ether is flammable in air and explosive in oxygen and nitrous oxide. The safest practice is to not use ether with diathermy. The ether vapor is flammable within the patient(airway, lung or stomach) and within 30 cm of the anaesthetic circuit. No sources of ignition are permitted within 30 cm of this zone of risk. Scavenging must always be carried out if possible. If diathermy must be used with ether, oxygen must be turned off well beforehand.

Halothane

Halothane is sweet smelling, non-irritant, non-flammable and induces anaesthesia more quickly than ether. If planning an inhalational anaesthetic, halothane may be used for induction to avoid the problems with ether and then change over to ether.

Halothane inhalational induction may be a good choice of induction especially for children and difficult intubations.

Halothane is not an analgesic. It cannot be used as the sole anaesthetic agent and patients must receive analgesia. Halothane must be combined with intravenous analgesia or may be used in combination with trichloroethylene, a good analgesic but poor anaesthetic.(Two vaporizers are connected. Trichloroethylene is delivered at 0.5% to 1% to provide analgesia and the concentration of halothane is varied to maintain anaesthesia).

 Never connect any Vaporizer containing halothane to the inlet port of an EMO (Epstein,Macintosh, Oxford) Vaporizer. Halothane will corrode the Vaporizer. It is safe to connect a halothane Vaporizer (such as an OMV) to the outlet port of the EMO. The halothane Vaporizer must be nearest the patient. Turn the trichloroethylene off a few minutes before the end of the operation as it has a slow recovery.

Halothane is potent and overdose is easy. It must always be given though a calibrated vaporizer. Using a Vaporizer not made for halothane will give an incorrect concentration.If halothane is put into a Vaporizer calibrated for a more volatile or potent agent, the effect will be a lower concentration. If halothane is put into a Vaporizer calibrated for a less volatile or potent agent, the effect will be a higher concentration. Vaporizers must be serviced regularly.

Untrained staff must not use halothane.

Halothane will cause dose-dependent respiratory depression resulting in hypoxia.Halothane produces dose dependent increases in the rate of breathing. 1 MAC of halothane will approximately double the respiratory rate. Tidal volume is decreased. The patient will have rapid shallow breathing. The increase in the rate of breathing is insufficient to offset the reduction in tidal volume, causing a reduction in minute ventilation and elevation of arterial carbon dioxide (PaCO₂). Halothane depresses the ventilatory response to arterial hypoxia that is normally mediated by the carotid bodies.1.1 MAC will produce 100% depression. Oxygen must be provided for halothane anaesthesia.

Halothane produces dose dependent cardiovascular depression. 1 MAC of halothane can cause a 20% reduction in blood pressure as a consequence of decreases in myocardial contractility and cardiac output (decrease in stroke volume). Peripheral vascular resistance is not significantly altered by halothane.Halothane slows conduction of cardiac impulses though the atrioventricular node and the His-Purkinje system. A junctional rhythm causing a fall in blood pressure is common.Halothane also reduces the dose of adrenaline (epinephrine) required to produce ventricular arrhythmias. The dose of submucosally injected adrenaline necessary to produce ventricular arrhythmias in 50% of patients receiving 1.25 MAC of halothane is2.1 micrograms/kg. It is likely that cardiac dysrhythmias due to adrenaline will persist until the halothane concentration is less than 0.5%. Injection of adrenaline by the surgeon may be dangerous and the doses, and the patient, need to be carefully monitored.

Halothane will cause uterine relaxation. This may be useful to help manual removal of the placenta but can cause increased uterine haemorrhage when given in concentrations above 0.8%. 0.5 MAC of halothane with 50% nitrous oxide will ensure amnesia during caesarean section and has no effect on the foetus and does not increase uterine bleeding.

Postoperative shivering may occur. Halothane increases cerebral blood flow (and an increase in intracranial pressure) but a reduction in cerebral oxygen requirement.Halothane hepatitis is extremely rare (1:30,000). Volatile anesthetics can trigger malignant hyperthermia.

Inhalational induction requires the gradual increase of inspired concentration up to 3% .A maintenance dose is 1 to 2% for spontaneously breathing patients and 0.5 to 1% during IPPV. Recovery is quick. 

Trichloroethylene

Trichloroethylene is a colorless, non-irritant, safe agent that is decomposed by light. It maintains cardiac output and provides good analgesia but it cannot be used as a sole anaesthetic agent. Trichloroethylene has a SVP of 60 mmHg so it is impossible to deliver a high enough concentration to cause anaesthesia. A blood/gas coefficient of 9 means that induction and recovery is slow (turn off at least 10 minutes before the end of anaesthesia). Higher concentrations of trichloroethylene can cause arrhythmias and adrenaline should not be administered with trichloroethylene. Trichloroethylene causes an increase in respiratory rate but a decrease in tidal volume so that PaCO₂ rises and

PaO₂ falls in spontaneously breathing patients. It is a poor muscle relaxant and causes more PONV than halothane.

Trichloroethylene must never be used in a circle system with soda lime as the toxic compounds phosgene and carbon monoxide are produced.

Trichloroethylene is an excellent agent to use as background analgesia. Initial dose is 0.5to 1%, reducing to 0.2 to 0.5%.

Enflurane

Enflurane is similar to halothane. It is a colorless volatile liquid with a SVP of 175 mmHg, blood gas coefficient of 1.9 and MAC of 1.7.

Enflurane causes less sensitization of the heart to adrenaline than halothane and a greater fall in blood pressure but a similar fall in cardiac output.

The rise in cerebral blood flow (and intracranial pressure) is less than with halothane but enflurane can produce epileptic waveforms on EEG, especially above 2 MAC and if PaCO₂ is less than 30 mmHg.

20% of enflurane is metabolized, producing fluoride ions. Peak fluoride ion concentration after prolonged enflurane administration (2.5 MAC hours) may reach 20 microM/l (1/3 the level considered to be toxic).

Halothane is a much superior agent for inhalational induction.

Isoflurane

Isoflurane has a SVP of 250 mmHg, blood gas coefficient of 1.4 and MAC of 1.15. It has fast recovery but is a very difficult agent to use for inhalation induction because of its irritating bad smell.

Isoflurane does not sensitize the heart to adrenaline. It causes a greater fall in blood pressure than halothane but minimal fall in cardiac output. Isoflurane is a more potent coronary artery vasodilator than halothane or enflurane in animals and patients with coronary artery disease.

 Sevoflurane

Sevoflurane has a SVP of 160 mmHg, blood gas coefficient of 0.6 and MAC of 2.0. It is sweet smelling and non-irritant. These features make it an excellent induction agent with rapid onset and recovery.

Methoxyflurane

Methoxyflurane is a potent (MAC 0.2) anaesthetic and powerful analgesic but with very slow onset and recovery (blood gas coefficient 13). The very low SVP (23 mmHg) of methoxyflurane made it difficult to vaporize. The metabolism of methoxyflurane releases fluoride ions that can cause high output renal failure.

Cyclopropane

Cyclopropane has fast onset and recovery (blood gas coefficient 0.45). It causes marked respiratory depression and ventricular arrhythmias are common with hypercapnia,hypoxaemia and atropine or adrenaline administration. Nausea and vomiting are common. It is explosive in oxygen and air.

Nitrous Oxide

Nitrous oxide is a colorless, sweet smelling, non-irritant and non-flammable gas. It is a fair analgesic and has minimal cardiovascular and respiratory effects. Nitrous oxide hasa rapid onset and recovery (blood gas coefficient 0.47) but is a very poor anaesthetic (MAC 104%).

There are several disadvantages. Nitrous oxide is relatively expensive, does not produce muscle relaxation, increases cerebral blood flow and may increase pulmonary vascular resistance.

Nitrous oxide has a 35-fold greater blood gas coefficient than nitrogen (0.013). For every molecule of nitrogen removed from airspace, 35 molecules of nitrous oxide will pass in. During anaesthesia, nitrous oxide diffuses into any body cavity, which contains air. This includes the middle ear, gut and a pneumothorax. 70% nitrous oxide will double the size of a pneumothorax in 10 minutes. It must not be given to a patient with an untreated pneumothorax.

Nitrous oxide can cause diffusion hypoxia. (At the end of an operation nitrous oxide rapidly leaves the blood and passes out though the lungs. This can dilute the oxygen in the lungs). All patients should receive oxygen at the end of the anaesthetic.

Nitrous oxide can be used as a simple analgesic for mild to moderate pain. It may be used in combination with oxygen and another volatile anaesthetic for the maintenance of anaesthesia.

Agent	Blood Gas Coefficient	SVP mmHg (kPa)	BP	MAC
Ether	12	425 (59)	35	1.9
Halothane	2.4	243 (32)	50	0.76
Enflurane	1.9	175 (24)	56	1.68
Isoflurane	1.4	250 (33)	49	1.3
Sevoflurane	0.69	160 (21)	58	2.4
Nitrous oxide	0.47		-88	105
Desflurane	0.42	673 (88)	23	6
Trichloroethylene	9	60 (8)	87	0.17
Methoxyflurane	13	23 (3)	105	0.2
Cyclopropane	0.45		-33	9.2