eLFH - Inhaled Anaesthetic Agents and Oxygen Toxicity Flashcards
Mechanism of oxygen toxicity
Note complex and not fully understood
Hyperoxia produces highly oxidative, partially reduced active metabolites
Radicals interfere with basic metabolic pathways and enzyme systems - especially those containing sulphydryl groups
Examples of highly oxidative, partially reduced active metabolites produced in hyperoxia
Hydrogen peroxide
Hydroxyl radicals
Oxygen free radicals - e.g. Superoxide
Types of oxygen toxicity triggers
Normobaric oxygen
Hyperbaric oxygen
Effects on pulmonary function exerted by hyperoxia in normobaric conditions
Range from atelectasis to tracheobronchitis to severe alveolar injury
Direct dose dependent and time dependent effect
Process of hyperoxia leading to impaired pulmonary function
Hyperoxia
Endothelial neutrophil and macrophage recruitment
Release of inflammatory mediators
Reduction in surfactant production
Interstitial oedema
ARDS
Impaired gas exchange + Hypoxia
Pulmonary fibrosis at 1 week
Normobaric oxygen at different FiO2 and time before detectable changes to pulmonary function
FiO2 1.0 = 12 hours
FiO2 0.8 = 24 hours
FiO2 0.6 = 36 hours
FiO2 0.5 = indefinitely
Effect of high FiO2 on lung volumes
Absorption atelectasis
May be responsible for reduced vital capacity and increased shunt fraction
Results by 2 mechanisms
Mechanism 1 for absorption atelectasis
Seen in dependent areas of lung
Airway occlusion forms trapped gas pockets - no longer ventilated
Initial pressure in these pockets is atmospheric, but as gas exchange occurs total partial pressure becomes sub-atmospheric
Continued gas exchange down partial pressure gradients results in collapse of these pockets and absorption atelectasis occurs
Mechanism 2 for absorption atelectasis
Inspired gas ventilates alveolar units and alveolar uptake removes this gas into blood
Alveolar volume is balance between alveolar ventilation and alveolar uptake
If alveolar uptake falls below a critical value, the alveolus will collapse
How does high FiO2 promote absorption atelectasis
On air, arterial PO2 is ~13 kPa
Extraction of 4.5 ml/dL of O2 by metabolically active tissue results in venous PO2 ~ 6.5 kPa
On FiO2 1.0, arterial PO2 is much higher ~ 89 kPa
Due to sigmoid shape of O2 dissociation curve, venous PO2 only increases by a fraction to ~7kPa
Therefore greater alveolar to mixed venous PO2 gradient created - stimulates more rapid O2 uptake and therefore faster alveolar collapse by mechanism 1 and 2
Special considerations for neonates younger than 44 weeks post conception age
Avoid concentrations of O2 greater than 10.6 kPa for more than 3 hours
Therefore saturations kept around 90%
Reason for lower oxygen concentrations and saturations in neonates younger than 44 weeks
Hyperoxia in these neonates associated with:
- Retinopathy
- Necrotising enterocolitis
- Bronchopulmonary dysplasia
- Intracranial haemorrhage
Reason for maintaining normoxia post cardiac arrest or traumatic head injury
Initial hyperoxia is associated with worse outcomes
The Bert effect
Effect of hyperoxia on the CNS under hyperbaric conditions
The Bert effect at 2 atmospheres
Paraesthesia
Nausea
Facial twitching
Myopia
The Bert effect at above 2 atmospheres
Convulsions may predominate
The Smith effect
Pulmonary changes seen from hyperoxia under hyperbaric conditions
Similar picture to pulmonary changes seen under normobaric conditions but are accelerated
Inhalation anaesthetic agents compartment model
Inhaled anaesthetic agents conform to a multi-compartment pharmacokinetic model
Lungs considered as additional compartment in series from which central compartment is dosed
At equilibrium:
Agent partial pressure in alveoli = Partial pressure in central compartment (arterial) = Partial pressure at effect site (brain)
Factors which affect inhalation agent distribution from central compartment (i.e. arterial compartment)
Peripheral compartment blood supply
Compartment capacity (tissue : gas coefficient)
Factors which determine uptake of inhalation agent from lungs to central (arterial) compartment
Alveolar fractional concentration
Blood : gas coefficient
Cardiac output
Alveolar : venous gradient
Concentration effect and Second gas effect
Determinants of alveolar fractional concentration (FA)
Alveolar ventilation - increases FA
Fi - increases FA
FRC - decreases FA (acts as reservoir which prolongs filling time and reduces rate of FA rise)
Effect of alveolar fractional concentration on inhalation agent anaesthesia time
Alveolar fractional concentration provides driving force for diffusion of agent into blood
Higher FA reduces time for onset / equilibrium
Blood : gas coefficient definition
Ratio of amount of anaesthetic agent in the blood to that in gas when the 2 phases are of equal volume and pressure in equilibrium at 37 degrees Celsius
Effect of Blood : gas coefficient on speed on inhalation agent onset
Lower blood : gas coefficient have greater speed of action
Lower solubility results in more rapid build in arterial and effect site partial pressure of agent
Partial pressure of agent determines effect
Effect of cardiac output on anaesthetic agent speed on onset
At low CO, the effective volume is reduced and therefore alveolar concentration and blood concentration equilibrate quicker
Therefore low CO produces more rapid induction
Explains why elderly / critically unwell patients require lower doses of anaesthetic agent
Why is effect of cardiac output on anaesthetic agent onset less pronounced with more modern anaesthetic agents
Lower blood solubility of modern agents
Alveolar : venous gradient definition
Gradient between alveolar partial pressure of anaesthetic agent and venous partial pressure
Not present at induction but generated as an agent leaches from peripheral compartments into venous system - reduces alveolar : venous gradient and drives agent into the arterial circulation
Concentration effect description
Explains attributes of nitrous oxide and xenon as carrier gases
Rate of rise in alveolar fractional concentration is disproportionate to the Fi when high concentrations of carrier gas are given
Concentration effect explanation
Occurs with carrier gases as they are non potent and therefore delivered at high fractional inspired concentration
As carrier agent diffuses from alveolus into bloodstream, large percentage of alveolar volume is lost
Further gas is thus drawn into alveolus disproportionately increasing the concentration of the other carried gases (augmented ventilation)
High volumes of carrier gas required
Effects of the concentration effect
Second gas effect
Diffusion hypoxia
N2O FA/Fi profile
Second gas effect
Augmented ventilation increases alveolar fractional concentration of both carrier gas and the anaesthetic agent
This provides greater gradient to drive agent into bloodstream and increases uptake
Diffusion hypoxia
Reverse of the second gas effect
During emergence, high volumes of N2O diffuse into alveolus increasing its FA but therefore reducing FA of oxygen
May lead to hypoxaemia if not battled by supplementing FiO2
N2O FA/Fi profile
Uptake rate of 70% N2O is higher than Desflurane, whereas uptake rate of 20% N2O is lower than Desflurane
At high volumes, the concentration effect overcomes the advantage that Desflurane has over N2O in terms of lower solubility
Mechanism of anaesthetic agents inducing hypnosis
Poorly understood because what causes consciousness awareness is unanswered
May impair connectivity between networks of higher order neurones found within frontal parietal cortices and thalamus
Theory that anaesthetic agents act at specific target sites - stimulate inhibitory receptors or inhibit excitatory receptors
Historic theories of anaesthetic agent mechanisms of action that have now largely been excluded
Meyer-Overton - Lipid solubility
Critical volume - change in membrane volume
Lateral phase separation - change in membrane fluidity
Receptor targets of general anaesthetics
Gamma aminobutyric acid A (GABA a) receptors
Strychnine sensitive glycine receptors
Glutamate receptor family (NMDA, AMPA)
Nicotinic acetylcholine receptors
5-Hydroxytryptamine receptors (5HT)
Mainly post synaptic receptors
Inhibitory neurotransmitters
GABA
Glycine
Stimulatory neurotransmitters
Glutamate (NMDA and AMPA receptors)
Nicotinic acetylcholine
Ionotropic receptors (ion channels)
GABA A
NMDA
Metabotropic receptors (G protein coupled receptors activating intracellular pathways)
GABA B
Glutamate subtype
Adreno-receptors
General anaesthetic agents which act on GABA A receptor
Nearly all inhalation and intravenous agents
GA agents which inhibit NMDA receptors
Ketamine
Nitrous oxide
Xenon
Receptor actions of Propofol and Thiopentone
Stimulate GABA receptors
Stimulate Glycine receptors
Inhibit neuronal ACh receptors
Subtypes of GABA receptors and their features
GABA A - post synaptic, ionotropic
GABA B - pre synaptic, metabotropic
Structure of GABA receptors
Pentameric (5 subunits)
Over 30 isomers - may be composed of alpha, beta, gamma, delta, echo or pi subunits
Predominant subunit configuration of GABA recpeptors
2 alpha subunits
2 beta subunits
1 gamma subunit
Action of GABA receptors
Inhibitory
Binding of natural ligand GABA to alpha subunit open central Cl- ion channel
Influx of chloride ions hyperpolarises the neuronal membrane
Therefore inhibits action potential transmission
Inhalation anaesthetic agent binding site on GABA receptor
Alpha subunit
Intravenous anaesthetic agent binding site on GABA receptor
Beta subunit
Benzodiazepine binding site on GABA receptor
Alpha subunit / alpha-gamma interface
What determines pharmacological actions of different anaesthetic agents given their binding sites on GABA receptors
Different subunit configuration of different GABA receptor isomers and the location within the CNS of each isomer
Structure of NMDA receptor
4 subunits
2 types of subunit - GluN1 and GluN2
Action of NMDA receptors
Excitatory
Natural co-ligands Glutamate and Glycine bind at GluN1 subunits and GluN2 subunits respectively
Opens calcium ion channel
Influx of Ca2+ modulates post synaptic actions
Action of ketamine, nitrous oxide and xenon
Non-competitive NMDA receptor antagonists
NMDA acronym stands for
N-Methyl-D-Aspartate
Action of Magnesium on NMDA receptors
Mg2+ binds to open NMDA channel inhibiting passage of Ca2+
Actions of alcohol on NMDA receptor function
Alcohol mediates its effects of tolerance, dependence and withdrawal symptoms via its effect on NMDA receptor number and function
