Volatile Anaesthetics

Inhaled agents

• Current - Nitrous Oxide, Halothane, Enflurane, Isoflurane, Sevoflurane, Desflurane
• Previous - Chloroform, Cyclopropane, Methoxyflurane, Trichloroethylene, Fluroxene, Diethylether
• Others - Xenon , Argon, Nitrogen, Compound 485, Thiomethoxyflurane, n-Pentane, Hydrogen, Diosychlorane.

1. The GABA _A receptor-chloride channel is a ligand-gated inhibitory complex that contains modulatory sites for benzodiazepines, barbiturates, etomidate, propofol, steroid anaesthetics and volatile anaesthetics.   Intravenous and inhalational anaesthetis also modulate the presynaptic release or uptake of GABA
2. There are at least six different classes of voltage-sensitive calcium channels , at least three have been linked to the action of volatile and intravenous anaesthetics
   • T-type - T-type calcium channels are important in controlling the state of the postsynaptic membranes in the brain.  Volatile anaesthetics depress this receptor in several cell types which, at least in part, accounts for their anaesthetic action.
   • L-type - Barbiturates, etomidate, ketamine, propofol and alphaxalone inhibit dihydropyridine binding, but not verapamil binding to this receptor
   • N-type
   • Isoflurane inhibits neuronal calcium channel currents by enhancing current inactivation and prolonging the recovery time after inactivation
3. Nitrous oxide, Xenon and ketamine preferentially act on the N-methyl-D-aspartate (NMDA ) receptor
4. The Muscarinic complex is important in memory and consciousness.
   • Desflurane has a biphasic effect on m1 signaling, enhancing at a low concentration but depressing at higher concentrations.
   • Isoflurane has no effect on m1 signaling, but profoundly inhibits m3 signaling
   • Sevoflurane depresses the function of m1 receptors in a dose-dependent manner
   • Halothane depresses the m1 and m3 receptors in a dose-dependent manner
5. The neuronal nicotinic acetylcholine receptors (nACh) have their slow desensitised conformational state stabilised by all general anaesthetics.
6. Halothane, enflurane, isoflurane, desflurane and sevoflurane, at clinical concentrations, significantly suppress voltage-gated sodium channels.

B iokinetics

C hemistry

D ose - Given via a calibrated vaporiser

A standard measure of potency is the Minimal Alveolar Concentration. This is the alveolar concentration of an agent, at one atmosphere required to produce immobility in 50% of patients when exposed to a noxious stimulus (defined as skin incision in humans).

Note no mention of the times involved are mentioned and one presumes steady state.

• MACawake - Allows a voluntary response to commands in 50% of patients, this is used to imply the amnestic dose of the agent = 0.7 MAC for Halothane
• MAC95 - Prevents 95% of patients responding = 1.3 MAC for Halothane
• MAC _BAR - Blocks Adrenergic Response in 50% of patients = 1.5 MAC for Halothane
• MAC _BAR95 - Blocks 95% of patients = 2 MAC for Halothane

MAC is "Decreased" by

• Nitrous Oxide (MAC are additive so another volatile will also decrease the MAC)
• Premedication (Amnesiac effects of drugs are additive)
• Age (MAC decreases with age)
• Acute alcohol intoxication Hypothermia (The actual change in MAC per degree is not the same for all the volatiles)
• Hypotension (Presumed to be due to the more rapid rise in alveolar concentration - Time)
• Hypercarbia (Carbon Dioxide >120mmHg has been used as an anaesthetic - Hickman)
• Sympathetic decrease (Centrally acting drugs - clonidine, reserpine, methyldopa, pancuronium)

MAC is "Increased" by

• Age (MAC is highest at 6 months)
• Chronic alcohol abuse (enzyme induction)
• Sympathetic increase (Central drugs - Ephedrine, amphetamines, cocaine)
• Hypermetabolic states (Thyrotoxicosis, pyrexia)

E ffects

F ormulation

I ndications

• Gas induction Sevoflurane > Halothane > Isoflurane >>> Enflurane > Desflurane
• Maintenance of anaesthesia

Contra indications

• Malignant hypermetabolic syndrome precipitation
• Calcium channel blocking agents - usually well tolerated providing left ventricular function is good

Controversies

Halothane Hepatitis

Epidemiology: ~1/35 000 patients on exposure to halothane will develop hepatic necrosis.

Risk factors that increase the chances are:- late middle age (50), obesity and being female.

Diagnosis: All other causes of jaundice must be considered and excluded before a diagnosis of halothane related hepatitis can be made. The most important is to rule out the various types of viral hepatitis, which may not be serologically positive in the early postoperative period. Other causes include

1. Surgical complications, especially bile duct surgery,
2. Peri-operative hypotension;
3. Intra-abdominal sepsis and / or septicaemia;
4. Infections with CMV, EBV and toxoplasmosis;
5. Reactions to other drugs used before or during surgery;
6. Sickle-cell crisis

Mechanism of toxicity:

Type I halothane hepatitis : This is an asymptomatic rise in serum transaminases 1-2 weeks after exposure, that resolves without treatment. Histologically there is an acute hepatitis like picture. There have been many theories about the causation of type I hepatitis.

Direct allergic reaction to the intact halothane molecule. This is not the case as a protein complex is needed to trigger an immunological event. Unfortunately this simplistic theory gave rise to the erroneous impression that halothane is safe to use again after 3 months, in spite of an earlier reaction.

Direct biochemical destruction of the liver by reductive metabolic intermediates analogous to the liver damage caused by the free radical species formed during the metabolism of carbon tetrachloride and chloroform.

Hepatic hypoxia can easily be precipitated by a minor degree of hypotension because of the loss of the hepatic artery buffer reserve. The first step in the reductive pathway is believed to be an insertion of a single electron into the halothane molecule to produce a highly reactive metabolite which then undergoes debromination to another free radical intermediate. The simplistic approach is that liver macromolecules interact with metabolic intermediates or free radicals. Free radicals are moieties capable of independent existence that contain one or more unpaired electrons. These free radicals capture electrons from adjacent molecules and produce a chain reaction in which free radicals beget other free radicals which, in effect go on a destructive rampage. This may cause an autocatalytic peroxidative chain reaction in the liver, leading to breakdown and necrosis of essential fatty acids, lipoproteins and cell membranes.

Type II halothane hepatitis :

This reaction is uncommon and unpredictable, there is clinical and laboratory evidence of severe hepatic necrosis. There is no relationship between the amount of halothane used and the likelihood of this reaction, but there does seem to be a correlation between the amount of halothane used and the severity of the liver failure. Onset may be by the 7 ^th day after administration or relatively delayed compared to direct hepatotoxic drugs e. g. paracetamol, for up to 28 days. It is accompanied by the rapid development of jaundice, raised liver enzymes, pyrexia, arthralgia, rash, and direct evidence of immune sensitisation - eosinophilia, circulating immune complexes and a variety of autoantibodies to normal tissue components. There is characteristically a very high mortality rate. There are several case reports of halothane hepatitis in children and in anaesthetic personnel.

There is now strong evidence that this is due to an immune response directed against hepatocytes. The most convincing evidence for this theory is that serum from patients with type II halothane hepatitis contains antibodies that react with an acyl halide that is covalently bounded to liver cell membranes (N-e-Lysine). This acyl halide (CF ₃ COCl) acts as an epitope or hapten that is presented to the immunocompetant cells, setting up and antibody reaction. The acyl halide is a mandatory precursor to the production of Trifluoroacetic acid (TFA), the major oxidative metabolic breakdown product of halothane, enflurane, isoflurane and desflurane. Why only a small percentage of patients amount an immune response appears to be related to a variety of susceptibility factors

1. Variability in the levels of expression of cytochrome P450 isoenzyme
2. Abnormal expression of the protein bound epitope from the endoplasmic reticulum to the cell surface.
3. Variability of lymphocyte damage by electrophilic metabolites
4. Variability of immunological factors
5. Variability of the natural tolerance to the protein bound epitope.

This has now given rise to the theory that if no reaction to halothane has occurred within 28 days after exposure it is probably safe to give halothane again, but that if there was any form of reaction to an halothane exposure it is never again safe to give halothane. This leads to a practical difficulty, which is that Boyle’s machines that have been used for halothane anaesthesia continue to emit halothane for some time after the agent has been removed. This is due to absorption of halothane into the plastic components of the system providing a reservoir. The anaesthetic machine should be flushed free of halothane with 100% oxygen at a flow rate of 8L/Hr for 8 hours

Sevoflurane toxicity

Renal toxicity

Fluoride induced

Inorganic fluoride nephrotoxicity was first recognised in 1960 with the introduction of methoxyflurane. A serum level > 50mmol/L over a prolonged period of time i. e. the area under the graph, was associated with polyuria, proteinuria, glycosuria, impaired renal concentrating ability with a lack of response to vasopressin and an increased serum sodium, urea, creatinine and osmolarity. Sevoflurane metabolism readily releases inorganic fluoride with concentrations exceeding 50mmol/L after 2 MAC hours. However after extensive use for prolonged periods of time in Japan there have been no reports of renal dysfunction - Why?

The peak fluoride level is short lived in sevoflurane anaesthesia because the low blood/gas solubility coefficient allows rapid removal of the agent via the breath. This decreases the area under the curve considerably.

The fluoride liberated during methoxyflurane anaesthesia appeared to be produced in the kidney and was able to cause the damage directly. Sevoflurane is metabolised four times less readily in the kidney with lower fluoride levels within the kidney.

Compound A induced

Sevoflurane undergoes spontaneous degradation, to compound A-E, when exposed to high temperatures (>50 ^o C) that occur in sodalyme and baralyme. Compound A has been found to be nephrotoxic in rats but never in humans - Why?

The amount of compound A is dependant on the temperature of the absorber, Sodasor is the most commercially used product and produces the lowest temperature 40 ^o C because of the lack of KOH.

The fresh gas flow used is very seldom minimal today and so helps wash out compound A

The nephrotoxicity in rats is because of b lyase metabolism, in the rat kidney, to a reactive thiadacyl intermediate that does the damage. Human kidney renal b lyase activity is much lower than the rat’s.

Hepatitis

Oxidative metabolism of sevoflurane produces no reactive intermediaries and so is incredibly unlikely to ever be associated with an immune linked hepatotoxicity. This makes sevoflurane the agent of choice in a patient who has documented sensitivity to the reactive intermediary produced during trifluoroacetic acid production.

Guedals stages of anaesthesia

Desflurane vaporiser

Desflurane with its boiling point of 22.8 ^o C if administered in a conventional plenum vaporiser could produce disastrous changes in output with small increases in temperature. If the vaporiser temperature rose above the boiling point a continuous flow of gaseous agent would be produced until all the liquid evaporated, or until the latent heat of vaporisation resulted in the temperature being lowered below the boiling point. The boiling point is so close to that of room temperature, that so called "temperature compensators" would be inadequate. The alternative approach, used with nitrous oxide, to contain the liquid in a cylinder and draw off the gas is also impractical because at room temperature the saturated vapour pressure is too low. These are overcome using a vaporiser with a sump heater so that vapour pressure is raised to around two atmospheres absolute pressure (37 ^o C) internally and then dispensed using a system of differential pressure transducers and variable resistance. The vapour can be mixed with fresh gas using a metering valve. The entire vapour pathway is heated to prevent the high partial pressure of the agent (potentially above the saturated vapour pressure at room temperature) from "raining out".

Xenon: A little more detail on the drug, just to tempt us!

Despite the high cost of xenon, xenon anaesthesia will become possible at a reasonable cost.  The hourly uptake of xenon decreases rapidly and with full recycling of the gas during closed circuit anaesthesia, xenon anaesthesia will be economically viable.

Physical properties

• Colourless, odourless, tasteless.
• Monatomic gas, atomic number = 54, molecular weight = 131,3
• Gas under normal temperature and pressure
• 9 stable isotopes.
• Freezing point -111,9 ^o C, Boiling point -108,1 ^o C.
• 4 times more dense than air.
• Nonflammable and will not support combustion.
• Diffuses freely through rubber and silicone components.
• Manufactured by separation from liquid air, often as a by product of steel making.

Anaesthetic agent

• First used in 1951 by Cullen on an 81yr old man having an orchidectomy..
• Very close to the ‘ideal agent’
• The very large electron shell of xenon ca be distorted and polarised by nearby molecules, creating a dipole.
• Xenon inhibits the plasma membrane Ca ²⁺ pump, altering excitability.  It inhibits the nociceptive responsiveness of spinal dorsal horn neurons.
• MAC = 71%. (With more widespread usage the Russians have noticed the MAC to be closer to 60%)
• Minimal haemodynamic effects.
• Lowest blood/gas partition coefficient = 0,115 of currently available inhalational agents.
• Low oil/water partition co-efficient of 20. 
• Rapid induction and eduction regardless of duration of administration
• Progressively decreasing xenon requirements during closed circuit anaesthesia makes it an economic viability.
• 4 stages of anaesthesia noted with 70% Xenon/ 30% oxygen.

1. Whole body paraesthesia & hypo-algesia.
2. Euphoria & increased psychomotor activity.
3. Analgesia with partial amnesia (after 3-4min).
4. Surgical anaesthesia with a degree of muscle relaxation.

• Equivalent analgesia when compared with equipotent doses of N ₂ O 
  • The analgesia produced by both gases is not reversible by naloxone.
  • The analgesic action of nitrous oxide involves the descending inhibitory system from the brainstem.  Xenon probably has a direct suppressive action on spinal dorsal horn neurons
• No occupational/ environmental disadvantages.

Specific effects on the body

• Respiratory
  • Central depression causes a decrease in respiratory rate with a compensatory increase in tidal volume and can progress to apnoea
  • Higher density and viscosity (compared with oxygen, air and  N ₂ O) theoretically makes xenon more likely to increase airway resistance. Clinically the airway resistance is slightly less than that seen with N ₂ O and it can be used safely in lung disease
  • Diffusion hypoxia is very mild as the blood/gas partition of Nitrogen (0.014) is only almost 10 times less than that of Xenon (0.115) as opposed to the almost 40 times less than Nitrous Oxide (0.47)
• Cardiovascular
  • No inhibitory effects on cardiac ion channels i.e. calcium, sodium and inward potassium channels.
  • No significant change in contractility, blood pressure and systemic resistance.
  • No sensitisation of the myocardium to adrenaline
  • May attenuate the  myocardial depressant effects of isoflurane.
  • In an animal study, xenon anaesthesia produced the highest regional blood flow to brain, liver, kidneys and GIT.  The control groups were 1% halothane in Nitrous oxide and thiopentone with fentanyl.
• Central nervous system
  • Xenon does not alter regional cerebral blood flow and autoregulation (Fink H, Blobner M, Bogdanski R, et al.   Effects of xenon on cerebral blood flow and autoregulation: an experimental study in pigs.  Br J Anaesth 2000; 84:221-225)
  • Inhaled xenon when used as a tracer for the measurement of cerebral blood flow increases cerebral blood flow, increases intracranial pressure and decreases cerebral perfusion pressure in acute head injury patients.  This is not associated with cerebral oligaemia or ischaemia.  This increase in cerebral blood flow is reversed by mild hyperventilation and so might have been a result of poorly controlled physiological variables.  Hypercarbic induced vasodilatation induced by the sedative effects of the inhaled xenon, and the stress effect of breathing a dense gas mixture.
  • At present its use in neurosurgery is controversial
• Renal
  • No data available.
• Endocrine/neurohumoral
  • Attenuates surgical stress due to analgesia.  Does not have any short or long term cortisol suppression effects.
• Toxicity
  • Platelet aggregation potentiated at 2atm (relevant to deep-sea divers).
  • No reported haematological toxicity.
  • Halted Cell Division
    • Mitosis is blocked at the metaphase-anaphase stage.  This is reversible on withdrawing xenon and administering calcium to the cell.
      • The most likely site for inhibition is the enzyme complex called Ca MK II
• Malignant hyperthermia
  • Seems not to trigger malignant hyperthermia.
• Metabolism and elimination
  • Unlikely to be involved in any biochemical events in the body.
  • Eliminated via the lungs.

Why Xenon is going to become a potential volatile anaesthetic.

• Decreasing manufacturing costs.
  • All new liquid air production plants have xenon extraction apparatus fitted
  • Loss of xenon from the atmosphere from satellite engines will cease from next year
  • SASOL has completed a very large production facility in South Africa
• Use in a fully closed breathing system
  • A computer controlled closed circuit machine is now commercially available - The Draeger/Physio partnership Physioflex machine
  • The ability of xenon to alter the speed of sound allows an reasonably accurate measurement
    • Measurement is generally difficult as
      • Xenon diamagnetic and does not absorb infrared radiation
      • Low reactivity precludes the use of specific fuel cell or electrode-type device
      • Mass spectrometry is expensive
  • Rotating vane meters are available to measure gas flow
    • Measurement is generally difficult as
      • Xenon causes Pitot tube and the variable orifice flowmeters to under - read
      • Hot-wired anemometers under-read.
• Medical license
  • Russian Federation in November 1999
  • German is expected in 2001

Practical usage

1. Nitrogen must be washed out by giving a high flow of pure oxygen for at least 5 minutes
2. Normal induction and muscle relaxation
3. After intubation connect the patient to an appropriate anaesthesia delivery system
4. The hypnotic concentration of 40-45%  is achieved after 1.5min
5. The anaesthetic concentration of 60-70% takes approximately 8 minutes.

Summary

• Colourless and odourless gas with no irritation to the respiratory tract.  Well tolerated with gas induction
• Low blood/gas and oil/water partition co-efficients allowing rapid induction and eduction
• The central nervous system effects are readily reversibly and there is no stimulant activity.
• Produces unconsciousness with analgesia and a degree of muscle relaxation
• MAC of 60-70% allows a reasonable inspired oxygen concentration
• It does cause respiratory depression, to the point of apnoea.
• It is cardiac stable.
• Not metabolised in the body and is eliminated rapidly and completely via the lungs.
• It is non toxic, has inherent molecular stability and does not form flammable mixtures.
• Has no long-term adverse effects with chronic exposure at low dose.
• Stable in storage, no interaction with anaesthesia circuits or soda lime.  Should not be used with rubber anaesthesia circuits as there is a high loss through the rubber
• Expensive - Routine usage will only be possible with a closed circuit delivery system that recycles xenon.

Owing to environmental concerns there may be no alternative but to use xenon even if it incurs an increase in cost.