Volatile agents Flashcards
What is MAC (minimum alveolar concentration)?
The minimum alveolar concentration of an inhaled anaesthetic at steady state that prevents reaction to a standard surgical stimulus in 50% of subjects at one atmosphere
MAC is a measure of potency
Lower MAC = more potent
More lipid soluble = more potent
Therefore MAC is inversely proportional to oil:gas partition coefficient (lipid solubility) = Meyer–Overton hypothesis
MAC should technically be expressed in kPa - however is often given as % because atmospheric pressure (101.3kPa) can be approximated to 100
Note: Easier to think of a ‘MAC’ as a unit of measurement?
What factors increase MAC?
(More anaesthetic needed)
Infancy
Hyperthermia
Hyperthyroidism
Chronic opioid use
Chronic alcohol use
Acute amphetamine intake
Hypernatraemia
What factors reduce MAC?
(Less anaesthetic needed)
Neonates
Elderly
Pregnancy
Hypotension
Hypothermia
Hypothyroidism
Acute opioid use
Acute alcohol intoxication
Chronic amphetamine intake
Lithium
Clonidine
Methyldopa
What is the oil:gas partition coefficient?
The oil:gas partition coefficient is a measure of lipid solubility
Higher oil:gas partition coefficient = higher lipid solubility
Lipid solubility is related to the potency of a volatile anaesthetic, as they must cross the BBB to reach the CNS and take effect
This is reflected in the Meyer-Overton hypothesis - MAC is inversely proportional to the oil:gas partition coefficient
Potency of inhaled anaesthetics from highest > lowest:
Halothane > isoflurane > enflurane > sevoflurane > desflurane > xenon > nitrous oxide
What is the blood:gas partition coefficient?
The blood:gas parition coefficient is a measure of the solubility of an agent in the blood relative to the partial pressure it exerts in its gaseous phase (when the two are of equal volume and pressure and in equilibrium at 37◦C)
Higher blood:gas partition coefficient = more soluble in blood
The blood: gas partition coefficient is related to the speed of onset and offset of the drug
The agent with the quickest onset / offset will have the lowest blood:gas partition coefficient (i.e. least soluble in blood) as it will have the highest partial pressure in blood
Speed of onset / offset from fastest > slowest:
Xenon > nitrous oxide > desflurane > sevoflurane > isoflurane > enflurane > halothane
Note: Nitrous oxide has a quicker onset / offset compared to desflurane despite a higher blood:gas partition coefficient due to the concentration effect
What factors increase the speed of onset of an inhaled anaesthetic?
The effect of an inhaled anaesthetic can be described in a three compartment model:
* PA = Alveolar partial pressure
* Pa = Blood partial pressure
* PB = Brain partial pressure
The partial pressure in PB is what allows the agent to take effect. Initially on inhalation the alveolar partial pressure (PA) increases, until it reaches equilibrium with the Inspired concentration of agent (FI) - When FA/FI = 1 equilibrium has been reached as can be shown on a wash-in curve
Then there will be transfer of the agent between compartments - initially PA > Pa > PB - equilibrium takes hours to occur and therefore may not be reached in practice
So in effect there are two mechanisms by which the speed of onset of an inhaled anaesthetic can be increased:
* Increasing alveolar partial pressure, reducing the time taking for FA/FI to reach equilibrium
* Increasing delivery of the agent to the effect site (CNS)
Factors which speed up onset of the inhaled agent include:
* High inspired concentration of agent - Leads to a quicker rise in PA and FA/FI = 1 reached more quickly
* Increased alveolar ventilation - FA/FI = 1 will be reached more quickly, and constant gas flow will replace any agent being taken up into the bloodstream
* Reduced functional residual capacity - Less gas for the agent to be diluted in, therefore PA is increased
* Reduced cardiac output - Less agent is transfered into the bloodstream, and therefore PA is increased
* Lower blood:gas partition coefficient (i.e. less soluble in blood) - Pa will be higher, and an increased concentration gradient with PB will increase transfer of the anaesthetic to the CNS
What is the concentration effect?
The concentration effect only occurs with nitrous oxide, because it is administered in much higher concentrations than other agents
The concentration effect is the disproportionate rate of rise of the FA compared to the FI at high concentrations, compared to when lower concentrations of nitrous oxide are inspired
This explains the faster rate of onset of nitrous oxide compared to desflurane, despite its higher blood:gas partition coefficient
Nitrous oxide is considered relatively insoluble, however is ~20x more soluble in blood than nitrogen. At high inspired concentrations, a large concentration gradient is produced which allows diffusion of nitrous oxide into the blood much more quickly than nitrogen can diffuse from the blood into the alveolus. As a result, the alveolus shrinks in volume and the remaining nitrous oxide (and other gases) will be concentrated. To prevent alveolar collapse, more gas is drawn in from the conducting airways (augmented ventilation). This gas also has nitrous oxide (and other inhaled agents if being used) and further increases the alveolar partial pressure of nitrous oxide
The below figure shows how FA/FI is higher after the same time period when 70% FiN2O is used rather than 20% FiN2O (making an assumption of 50% diffusion of N2O into the bloodstream in each case)
What is the second gas effect?
The second gas effect is a direct result of the concentration effect seen with high inspired concentrations of nitrous oxide
Oxygen / additional volatile agents will be concentrated by the rapid uptake of nitrous oxide and augmented alveolar ventilation
Increased alveolar concentrations of volatile agents will therefore result in reduced induction time
What is diffusion hypoxia and how does it occur?
Diffusion hypoxia can occur at the end of anaesthesia, and can be thought of as the reverse of the second gas effect
Nitrous oxide diffuses rapidly from the blood into the lungs, which dilutes all the alveolar gases, including oxygen
High FiO2 during emergence prevents diffusion hypoxia
Which volatile agents can be used for gas induction?
Sevoflurane, halothane, nitrous oxide
?Xenon
Enflurane no longer in regular clinical use but is non-irritant
Sevoflurane
Chemical
* Polyfluorinated isopropyl methyl ether
* Non-flammable
* Boiling point 58.6 degrees C
* SVP 22.7kPa at 20 degrees C
Uses - Commonly used for maintenance of general anesthesia, can also be used for induction due to its relatively pleasant, non-irritant odour
Presentation
* Stored as a clear, colourless liquid
* Formulated with >300ppm of water. When the concentration of added water is <100ppm sevoflurane may be degraded to produce highly toxic hydroflouric acid
Action
* Not fully understood
* Appears to act as agonist at inhibitory GABAA and glycine receptors, and antagonist at excitatory NMDA receptors
Dose - Relatively high (80) oil:gas partition coefficient resulting in reasonable potency and a relatively low MAC of 1.8%
Effects
* CVS - Reduction in BP primarily due to fall in systemic vascular resistance, with no effect on heart rate
* Resp- Reduces tidal volume, increases respiratory rate. Bronchodilation
* CNS - Cerebral vasodilation, reduced cerebral metabolic rate, may increase intracranial pressure
* Other - Uterine relaxation
Toxicity
* Compounds A-E may be produced when sevoflurane is used in the presence of carbon dioxide absorbents - particularly potassium hydroxide rather than sodium hydroxide based. Only compounds A and B are produced in relevant amounts - compound A is much potentially nephrotoxic. Not thought to be clinically relevant as only present in negligible amounts in humans even at low flow rates for prolonged periods
* May cause post-operative nausea and vomiting
* Malignant hyperthermia trigger
Absorption - Relatively low (0.7) blood:gas partition coefficient resulting in a relatively quick onset of action. Low blood solubility allows alveolar concentration to rise rapidly, and therefore fast onset (and offset) of anaesthesia
Distribution - Initial distribution to organs with high blood flow (brain, heart, liver, kidney) then to muscle and fat
Metabolism - Metabolized in the liver by CYP2E1 to produce HFIP, fluroide ions and carbon dioxide. Fluoride ions are associated with nephrotoxicity, but this does not appear to be clinically significant. Around 3-5% of a sevoflurane dose is metabolized
Excretion - Occurs via the lungs, majority as unchanged drug. Relatively quick offset
Desflurane
Chemical - A fluorinated methylethyl ether
* Boiling point of 23 degrees C
* High SVP of 88.5kPa at 20 degrees C
* Can be flammable at concentrations higher than 17%
* Significant greenhouse gas effect
* May produce carbon monoxide upon reaction with dry soda lime
Presentation -
* Desflurane has two physical properties, making it unsuitable for use with a conventional vaporizer. First, it has a very high SVP (88.5 kPa at 20°C). A conventional vaporizer would require high fresh gas flows to dilute it to within clinically useful concentrations, making it uneconomical
* Secondly, it has a low boiling point (23.5°C). At room temperature, it will intermittently boil resulting in large fluctuations in agent delivery. When boiling, there will be excessive agent delivery; however, it will then cool due to a large loss of latent heat of vaporization, resulting in an exponential decrease in SVP and under-delivery of agent
* An electronic ‘TEC6’ vaproizer is used which heats desflurane to 39 degrees C, and maintains a pressure of 2atm. Therefore a carrier gas is not used and gaseous desflurane is added directly to the fresh gas flow which is separate to the vaporizing chamber. The outflow from the vaporizing chamber will only open once the operating temperature is reached
Action - Major mechanism of action thought to be potentiation of inhibitory GABAA and glycine receptors, and antagonism at excitatory NMDA receptor
Dose - Desflurane has a low oil:gas partition coefficient of 29 resulting in lower potency, and a higher MAC of 6.6%
Effects
* CVS - Fall in BP, systemic vascular resistance. At higher concentrations may cause sympathetic stimulation resulting in increase HR and BP
* Resp - Respiratory depression causing reduced tidal volume, increased respiratory rate. Irritant therefore not used for gas inductions
* CNS - Cerebral vasodilation and increased cerebral blood flow, unclear effect on ICP
* Other - Uterine relaxation
Toxicity
* May cause post-op nausea and vomiting
* Malignant hyperthermia trigger
Absorption - Low blood:gas partition coefficient of 0.42 results in rapid onset / offset of anaesthesia. This makes it useful for prolonged or bariatric surgery
Distribution - To organs with high blood flow
Metabolism - Small minority (0.02%) undergoes metabolism
Excretion - Occurs via the lungs, majority unchanged. Rapid offset.
Isoflurane
Chemical - A halogenated ether
* Non-flammable
* Boiling point 48.5 degrees C
* SVP 32kPa at 20 degrees C
Presentation - Clear, colourless liquid with a pungent smell
Action - Major mechanism of action thought to be potentiation of inhibitory GABAA and glycine receptors, and antagonism at excitatory NMDA receptor
Dose - Isoflurane has a relatively high oil:gas partition coefficient of 1.4, which results in higher potency and a low MAC of 1.17%
Effects
* CVS - Fall in BP, SVR. HR relatively stable, may have reflex tachycardia
* Resp - Respiratory depression due to reduced tidal volume, respiratory rate may increase. Pungent and irritant, therefore cannot be used for gas inductions. Bronchodilation
* CNS - Cerebral vasodilation, may increase ICP
* Other - Uterine relaxation
Toxicity
* May cause post-op N+V
* The position of the C-F bond in isoflurane makes it more resistant to metabolism than enflurane. Fluoride ions produced are not associated with nephropathy
* May react with soda lime to produce carbon monoxide
* Malignant hyperthermia trigger
* Coronary steal syndrome
Absorption - Isoflurane has a relatively high blood:gas partition coefficient of 1.4, and so onset / offset is relatively slower than other agents (except halothane)
Distribution - To organs with high blood flow
Metabolism - Around 0.2% of an administered dose is metabolized by CYP2EI to produce metabolites such as HFIP, no significant toxic metabolites
Excretion - Majority of the dose excreted via the lungs. Metabolites excreted in the urine
Note - Enflurane is a structural isomer of isoflurane that is no longer used as it is pro-convulsant and metabolism produces fluoride ions shown to cause nephropathy. Enflurane has a higher MAC
Halothane
Chemical - A halogenated hydrocarbon containing bromine, chlorine and fluorine. C-F bonds are the most stable carbon-halogen bond
* Non-flammable at concentrations used clinically
* Boiling point 50.2 degrees C
* SVP 32kPa at 20 degrees C
Presentation
* Clear, colourless liquid with a sweet smell
* Must be protected from light
* Commerical preparation contains 0.01% thymol to prevent liberation of free bromine
* Can dissolve into rubber and may leach out into breathing circuits
Action - Appears to act as agonist at inhibitory GABAA and glycine receptors, and antagonist at excitatory NMDA receptors
Dose - Halothane has a high oil:gas partition coefficient of 224 resulting in high potency and a low MAC of 0.75%
Effects
* CVS - Decrease in BP due to fall in myocardial contractility, systemic vascular resistance and heart rate. Vagal stimulation
* Resp - Respiratory depression due to reduced tidal volume, although respiratory rate may rise. Non-irritant and therefore can be used for gas inductions. Causes bronchodilation
* CNS - Increases cerebral blood flow and intracranial pressure, more than other agents
* Other - Uterine relaxation
Toxicity
* Malignant hyperthermia trigger
* Sensitizes the heart to catecholamines which may lead to arrhythmias
* Halothane hepatitis
* - Type 1: Mild, transient post-op rise in serum liver enzymes possibly due to free radicals release during metabolism / hepatic hypoxia
* - Type 2: Fulminant hepatic necrosis and liver failure thought to be an autoimmune reaction to metabolites produced, therefore occurs after multiple exposures - recommended not to re-used within 3-6 months. Occurs rarely, but has a mortality of >50%
Absorption - Halothane has the highest blood:gas partition coefficient of 2.4, and so onset / offset will be relatively slow
Distribution - Distributes to organs with high blood flow
Metabolism - 20% of administered dose is metabolized in the liver via CYP2E1 by oxidation and reduction to produce metabolites such as trifluoroacetic acid (TFAA)
Excretion - Majority of administered dose excreted unchanged via lungs. Metabolites are excreted in the urine
Nitrous oxide
Chemical
* Boiling point -88.5 degrees C
* Critical temperature of 36.5 degrees C
* Critical pressure of 71.7 atmospheres
* Non-flammable, but supports combustion
* Nitrous oxide is produced by heating ammonium nitrate to 250 degrees C
Presentation
* Stored as a liquid in cylinders at a pressure of 44 bar at 15 degrees C. Cylinders are French blue / changing to white body with French blue shoulders. Filling ratio of 0.75 (0.67 in tropical regions)
* Gauge pressure of cylinder does not drop until all liquid nitrous oxide has been vaporized. Will continue to read at the saturated vapour pressure until this happens
* Pin index configuration 3 and 5
* Also can be used from pipeline at a pressure of 4 bar
Action - Non-competitive inhibition of NMDA receptor
Dose - Low oil:gas partition coefficient of 1.4 results in a low potency and a MAC of 105%, therefore cannot be used as a sole anaesthetic agent at standard atmospheric pressure
Effects
* CVS - BP relatively maintained. Decrease in myocardial contractility balanced by increased systemic vascular resistance
* Resp - Mild respiratory depression by reduced tidal volume, with some increase in respiratory rate. Non-irritant so often used in gas inductions.
* CNS - Increases cerebral blood flow, may be avoided in patients with raised intracranial pressure. Has analgesic properties
* Other - NO effect on uterine tone
Toxicity / side effects
* Causes post-op nausea and vomiting
* Causes increases in air-filled spaces such as pneumothorax
* Diffusion hypoxia
* Prolonged use leads to oxidation of the cobalt ion of vitamin B12, so that it is unable to act as the co-factor for methionine synthetase. This results in reduced synthesis of methionine, thymidine, tetrahydrofolate and DNA - and may cause megaloblastic changes in bone marrow or agranulocytosis
* Usually avoided in first trimester of pregnancy - teratogenic in rats but never proved in humans
* The maximum occupational exposure to nitrous oxide is 100ppm over 8 hours - should be avoided by proper scavenging
Absorption - Low blood:gas partition coefficient of 0.47 results in rapid onset / offset, further increased by the concentration effect. Also second gas effect when used in combination with other agents
Metabolism - None - minimal metabolism
Excretion - Unchanged via lungs
