Pharmacology: Nitrous oxide and Xenon

Nitrous oxide

Fast facts:

  • Method of action = N-methyl-D-aspartate receptor antagonist
  • Manufacture = Heating ammonium nitrate to 250◦C: NH4NO3 → N2O + 2H2O. Impurities include NO, HNO3, N2, NO2, NH3, and are removed through scrubbers, water and caustic soda
  • Appearance = Clear colourless gas, sweet smelling at room temperature
  • Critical temperature = 36.5 degrees celcius
  • Critical pressure = 72 bar
  • Saturated vapour pressure at room temp = 52 bar
  • Blood gas partition coefficient = 0.47 (rapid onset and offset of action)
  • Oil gas partition coefficient = 1.4
  • MAC = 105% (low potency)
  • Formula = N2O, atomic number N = 14, O=16, so molecular weight = 14+14+16 = 44
  • Cylinder pressure at room temp = 44 bar
  • Pipeline pressure = 4 bar
  • Filling ratio in temperate regions = 0.75
  • Filling ratio in tropical regions = 0.67
  • Control of substances hazardous to health (COSHH) regulation limit in the UK = 100ppm
Buy Nitrous Oxide Tanks & Cylinders | BOC UK Shop
N2O is stored as a liquid in french blue cylinders with a gauge pressure of 51 bar at 20 degrees Celsius
Anaesthesia UK : Introduction to medical gases
The gauge pressure bears no correlation to cylinder content until all remaining N2O is in the gaseous phase

Uses:

  • With 50% oxygen as entonox for sedation, labour analgesia
  • With volatile agents for higher MAC and additional analgesic benefit – particular recommendation by NAP 5 for GA sections as reduces the risk of awareness
  • Abused as ‘laughing gas’ in cylinders or balloons for a quick ‘high’
  • Possibly reduces post surgical pain and opioid induced hyperalgesia (ENIGMA-1 trial)

Effects:

  • Resp: Increased RR and small fall in tidal volume – minute volume unchanged
  • CVS: Mild direct myocardial depressant effects countered by increased sympathetic activity centrally – overall no change unless in cardiac failure or autonomic issues in which case it may significantly reduce cardiac output. Increase in pulmonary vascular resistance. ENIGMA-2 showed no increase in MI/death with N2O use.
  • CNS: Increases cerebral blood flow, metabolic rate and ICP
Particular pharmacological highlights:

Concentration effect = observed phenomenon that describes the disproportionate rate of rise of the alveolar fraction compared with the inspired fraction when high concentrations of N2O are inspired.

In simpler terms –

  1. Nitrous oxide moves across the alveolus rapidly due to high lipid solubility.
  2. The remaining gases in the alveolus (volatile agent, oxygen and nitrogen) are more concentrated.
  3. The pressure difference of volatile/oxygen/nitrogen between alveolus and blood increases.
  4. Volatile/oxygen/nitrogen diffuses quicker into the blood from the alveolus due to the higher pressure gradient.

Second gas effect = Direct result of concentration effect. Oxygen plus or minus volatile agents used alongside high concentrations of N2O will be concentrated by the rapid uptake of N2O and augmented alveolar ventilation. This leads to increased concentrations of oxygen and volatile agents resulting in a reduced induction time.

In simpler terms –

  1. Due to the concentration effect, the speed of onset of volatile agents increases.

Diffusion hypoxia = At the end of anaesthesia when N2O/O2 is replaced by air (N2/O2), the reverse of the second gas effect is seen. The volume of N2O entering the alveolus will be greater than the volume of N2 entering the pulmonary capillaries resulting in a dilution of all alveolar gases.

In simpler terms –

  1. At the end of anaesthesia, N2O is turned off, reducing the alveolar concentration of N2O.
  2. N2O from the capillaries diffuses very quickly into the alveolus from a high to lower concentration.
  3. If air (N2/O2) replaces the N2O/O2 anaesthetic mix, N2 takes longer to enter the capillaries to replace the volume of N2O that has escaped due to its lower fat solubility.
  4. More N2 remains in the alveolus alongside the N2O coming out of the capillaries, diluting the concentration of O2 in the alveolus and reducing amount of O2 entering the capillaries -> hypoxia.
  5. Avoid this by changing N2O/O2 mix to 100% O2.

Another scenario:

  1. A patient has a pneumothorax = a gas filled space between the parietal/visceral pleura
  2. N2O enters the airways and goes into the pneumothorax via the damaged alveoli
  3. Due to the concentration and second gas effects, N2O brings with it more O2/N2/volatile from the high to low concentration gradient
  4. This means that the gas filled space rapidly expands and can cause tension pneumothoraces
  5. Spaces such as pneumothorax, pneumoperitoneum, bowel gas, air emboli are compliant – they will increase in volume with transfer of N2O
  6. Non compliant spaces such as the cranium, middle ear and eye cannot increase in volume with N2O, so they will increase in pressure
  7. 50% N2O = 2 fold expansion. 75% N2O = 4 fold expansion.

Side effects:

  • Post operative nausea and vomiting
  • Diffusion hypoxia (see above)
  • Rapid expansion of a gas filled space – can occur in pneumothorax, vascular embolus, intestinal lumen, head, middle ear, pneumoperitoneum, eye. Also can increase tracheal cuff, laryngeal mask and pulmonary artery catheter cuff volumes and pressures.
  • DNA toxicity – N2O oxidises cobalt in B12 to prevent it from acting as a cofactor for methionine synthase. This reduces production of methionine, thymidine, tetrahydrofolate and DNA. This can cause agranulocytosis and megaloblastic changes even after a few hours. Treat with folinic acid and wait for new methionine to be synthesised.
  • Chronic B12 inactivation -> subacute combined degeneration of the cord
  • Teratogenicity – not used in 1st trimester
  • Reduces fertility and increases rate of spontaneous abortion in female theatre workers with chronic exposure
  • Environmental pollution – Has Ozone depleting potential due to NOx reactive intermediates that are produced with UV radiation. 3rd biggest contributor to greenhouse gases in the UK.

Entonox

50:50 mixture of N2O and O2.

UK BOC Online Shop: ENTONOX Compressed Gas
Stored as a gas in french blue cylinders with white shoulders. 137 bar.

Particular pharmacological highlights:

Poynting effect: The bubbling of oxygen through the liquid nitrous oxide increases the vapour pressure of the mixture to form a gas at pressures far exceeding those capable of liquidising nitrous oxide alone

Pseudocritical temperature = temperature at which entonox separates into its constituent parts (-7 degrees Celsius at 117 bar).

It is -30 degrees Celsius if delivered via pipeline at 4 bar = safer.
Separation is called ‘lamination’ and will leave oxygen gas above a layer of liquid nitrous oxide.

Importance of knowing this = if using a cylinder after separation, the inspired gas will produce little analgesia as it will contain mainly O2 in gaseous form. After the O2 empties, the mixture will become progressively potent and hypoxic as it approaches 100% N2O.

Xenon

Fast facts:

  • Inert, noble gas, odourless, no occupational or environmental hazards
  • MAC 71%, very low blood:gas partition coefficient (0.14). Onset and offset faster than desflurane and N2O, but less potent than all the volatiles
  • Manufactured by fractional distillation of air, costs 2000 times that of N2O
  • Slows RR and increases tidal volume so maintains minute volume
  • Higher density and viscosity than N2O
  • No diffusion hypoxia
  • Small decrease in HR
  • Variable increase in cerebral blood flow
  • Not metabolised in the body at all
  • Significant analgesic properties

References:

Pharmacology for anaesthetics and intensive care (Peck and Hill 4th Ed)

BJA CEACCP article March 2016 on N2O

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