Inhalational Anaesthetic Agents and Oxygen Toxicity

Question 1

What active metabolites does hyperoxia produce?

Answer 1

• highly oxidative, partially reduce active metabolites
  
  • hydrogen peroxide
  • oxygen
  • free radicals such as superoxide
  • most dangerous - hydroxyl radicals
• these interfere with basic metabolic pathways and enzyme systems, especially those containing sulphydryl groups

Question 2

How long before normobaric O2 therapy causes detectable changes in pulmonary function?

Answer 2

FiO2 1.0 - 12hrs

0. 8 - 24rs
1. 6 - 36hrs
2. 5 - indefinitely

Question 3

What effects can normobaric oxygen toxicity cause?

Answer 3

• atelectasis
• tracheobronchitis
• ARDS
• pulmonary fibrosis
• hypoxia due to impaired diffusion and gas exchange
• retrosternal discomfort
• carinal irritation
• cough
• dyspneoa

Question 4

Why can induction/extubation result in atelectasis?

Answer 4

Atelectasis can account for up to 10% of the lung volume when long pre-O2 times and high FiO2s are used.

This can reduce vital capacity and increase shunt fraction.

Question 5

What is the mechanism which causes absorption atelectasis in dependent areas of the lung?

Answer 5

• airway occlusion forms a trapped gas pocket which is no longer ventilated
• the pressure is initially atmospheric, but the total partial pressure of the mixed venous blood gases is subatmospheric
• continued gas exchange down the partial pressure gradients causes the pockets to collapse and absorption atelectasis to occur
• gas absorption occurs in 2 separate phases: rapid, when O2 is absorbed and slow, when N2 is absorbed

Question 6

What is the mechanism of absorption atelectasis?

Answer 6

• inspired gas ventilates the alveolar units and alveolar uptake removes this gas into the blood stream
• alveolar volume can be seen as a balance between this input (alveolar ventilation, VA) and output (alveolar uptake, Q)
• if the VA:Q ratio falls below a critical value, the alveolus will collapse

Question 7

Why does a high FiO2 promote absorption atelectasis?

Answer 7

Because the arterial PO2 is normally around 13 kPa in air, and tissues exctract about 4.5 ml/dL of O2, resulting in a venous PO2 of 6.5 kPa.

But on 100% O2, the arterial PO2 is 89 kPa. But the venous PO2 increases by only a fraction to about 7 kPa due to the shape of the oxyHb curve.

This creates a large alveoar-mixed venous PO2 gradient stimulating both rapid O2 uptake and faster alveolar collapse.

Question 8

What conditions does neonatal hyperoxia mediate pathological changes in?

Answer 8

• retinopathy of prematurity
• necrotising enterocolitis
• bronchopulmonary dysplasia
• intracranial haemorrhage

Question 9

How can you avoid retrolental fibroplasia?

Answer 9

Do not give O2 concentrations higher than 10.6 kPa for more than 3 hrs.

Saturations should be kept at 90% in babies younger than 44weks post conceptual age.

Question 10

How does O2 cause ventilatory depression in patients with chronic lung disease?

Answer 10

• those who retain CO2 become increasingly PO2 dependent
• so high inspired FiO2s can depress ventilation and cause apnoea
• need to target O2 therapy to treat life-threatening hypoxia whilst avoiding respiratory depression and arrest

Question 11

What is the Bert effect?

Answer 11

• describes the effect of hyperoxia on the CNS under hyperbaric conditions
• 2 atms- paraesthesia, nausea, facial twitching, myopia, olfactory and gustatory disturbances
• > 2-3 atms - convulsions

Question 12

What is the Smith effect?

Answer 12

• a similar picture to the pulmonary changes seen under normobaric conditions, although these changes are accelerated
• at 2 atms - vital capacity changes may occur at 4hrs, with significant symptoms at 10hrs

Question 13

What pharmacokinetic model do inhalational agents conform to?

Answer 13

A multi-compartment pharmacokinetic model.

The lungs may be considered as an additional compartment in series from which the central compartment is dosed. At equilibrium the partial pressure of an agent in the alveolus equals both that in the central compartment (arterial) and the effect site (brain).

P_A = P_a = P_B

Question 14

What are the factors that determine uptake of inhalation agents?

Answer 14

• alveolar fractional concentration
• Blood:gas coefficient
• Cardiac output
• Alveolar:venous gradient
• concentration and 2nd gas effect

Question 15

What is the alveolar fractional concentration (F_A) and how does this affect onset of anaesthesia?

Answer 15

• determinants of inhalation agent F_A are alveolar ventilation, Fi and FRC
• a high F_A will be achieved by increasing alveolar ventilation and/or Fi
• a high FRC acts as a large reservoir, prolonging filling time and reducing rate of rise of F_A
• F_A provides a driving force for diffusion of agent into arterial blood stream - a higher driving force = quicker onset time/equilibrium time

Question 16

What is the blood:gas coefficient?

Answer 16

• ratio of anaesthetic agent in the blood to that in gas when the 2 phases are of equal volume and pressure and in equilibrium at 37°C
• those with low B:G coeffiecient are faster onset
• lower solubility = more rapid build in arterial and effect site partial pressure
• agent partial pressure is what determines effect
• the effect of blood:gas coefficients on the equalibrium rates of the individual agents can be analyzed by comparing time to F_A/Fi of 1

Question 17

How does cardiac output affect onset of inhalational agents?

Answer 17

• at high CO the central compartment has a greater effective volume
• therefore takes a higher dose to achieve a given concentration
• at low CO the effective volume is reduced
• therefore lower dose to achieve concentration
• eg the elderly + critically ill need lower doses but have longer onset times as blood supply to the effect site is reduced

Question 18

What is the alveolar:venous gradient of inhalation agents?

Answer 18

• gradient between the P_A and the P_V
• not present at induction
• generated as agent leaches from peripheral compartments into venous system
• this reduces the gradient and drives the agent into the arterial circulation

Question 19

What is the concentration effect?

Answer 19

• observed phenomena by which the rate of rise in F_A is disproportionate to the Fi when high concentrations of carrier gas are given
• only occurs with carrier gases (N2O and xenon)
• these are non-potent and delivered at high fractional inspired concentration
• as the carrier agent exists the alveolus into the bloodstream, alveolar volume is lost
• further gas is drawn into the alveolus (augmented ventilation)
• disproportionately increasing the concentration of the other carried gas

Question 20

What is the second gas effect?

Answer 20

• augmented ventilation increases the F_A of both the carrier gas and anaesthetic agent
• this increases the gradient to drive the agent into the bloodstream and increases uptake

Question 21

What is diffusion hypoxia?

Answer 21

• the reverse of the 2nd gas effect
• during emergence high volumes of N2O diffuse into the alveolus, increasing it’s F_A but reducing the F_A of O2
• this can lead to hypoxaemia if not supplemented by FiO2

Question 22

What receptors are part of the super-family of transmitter-gated ion channels (TGIC)?

Answer 22

• GABA (gamma aminobutyric acid)
• NMDA, AMPA (glutamate receptor family)
• nicotinic acetylcholine receptors
• 5-hydroxytryptamine receptors

Question 23

Where are transmitter-gated ion channels normally found?

Answer 23

• mainly post synaptic
• integral to the fast inhibitory and excitatory CNS pathways of neurotransmission

Question 24

What are the inhibitory neurotransmitters?

Answer 24

GABA and glycine

Question 25

What are the stimulatory neurotransmitters?

Answer 25

Glutamate (NMDA, AMPA, kainate) and nicotinic ACh

Question 26

What receptors are ionotropic, how do they work?

Answer 26

• GABAA, NMDA
  
  • binding of ligand activates and opens central ion (ie a ligand-gated ion channel)

Question 27

What receptors are metabotropic and how do they work?

Answer 27

• GABAB, glutamate subtype, adreno-receptors
  
  • G-protein coupled receptors that activate intracellular pathways

Question 28

Which receptor is found to be affected by nearly all anaesthetic agents? What are the exceptions to this?

Answer 28

GABA_A

Exceptions - ketamine, nitrous oxide, xenon (inhibit NMDA receptors)

Question 29

What is the spinal analogue of the GABA receptor?

Answer 29

The glycine receptor (where inhalation agents may have a preferential effect)

Question 30

What receptors do propofol and thiopentone stimulate and inhibit?

Answer 30

Stimulate - GABA and glycine

Inhibit - neuronal ACh

Question 31

What is the structure of the GABA receptor?

Answer 31

• pentameric (5 subunits)
• main cerebral inhibitory receptor
• 2 subtypes:
  
  • GABA_A - post-synaptic: ionotropic
  • GABA_B - pre-synaptic: metabotropic
• Maybe composed of α,β,γ,δ,ε,pi subunits - over 30 different isomers
• The predominant subunit configuration is 2 α: 2 β: 1 γ
• Subunits vary according to anatomical site and function

Question 32

What is the function of the GABA receptor?

Answer 32

• binding of natural ligand GABA to alpha subunits opens a central Cl- conducting pore
• Cl- conductance hyperpolarizes the neuronal membrane inhibiting pathway transmission
• anaesthetic agents act as positive allosteric modulators at the GABA receptor
• they increase the ability of GABA to open the central pore, promoting Cl- conductance, prolonging hyperpolarization and augmenting neuronal inhibition

Question 33

How do IV anaesthetic agents affect GABA_A?

Answer 33

• bind at beta subunit and volatiles at alpha subunit
• benzos bind at the alpha subunit/alpha-gamma interface
• subunit config determines the actions of the anaesthetic agents at each receptor isoform

Question 34

What are the different pharmacological effects of benzodiazepines at the different GABA_A receptor subunits?

Answer 34

Question 35

What is the structure of the NMDA receptor?

Answer 35

• stimulatory neuro-receptor
• member of the glutamate ionotropic receptor family
• consists of 4 subunits - 2 types (GluN1 and GluN2) with many isoforms
• glutamate and glycine are the natural co-ligands that bind to the receptor to open a central Ca2+ conducting pore
• Ca2+ influx modulates many complex postsynaptic actions
• ketamine, nitrous oxide and xenon are non-competitive antagonists of the NMDA receptor

Question 36

What effects does alcohol have on NMDA receptors?

Answer 36

It inhibits NMDA function.

Question 37

Where are glycine receptors found?

Answer 37

In the brainstem and spinal cord where they function as the analogue of GABA_A

Inhaled agents may potentiate the effect of glycine in the spinal cord