Edinburgh 1996
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Edinburgh 1996 |
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THE IMPORTANCE OF THE PAST: A HISTORICAL PERSPECTIVE
Professor Alastair A. Spence
Edinburgh
The use of rebreathing with CO; absorption, although widely used in the United
States, has been largely avoided in the "British influenced" countries until the
1990's when the introduction of desflurane stimulated a renaissance of interest.
Even in the United States fresh gas flows of less than 3 litre min'' were rare
while any attempts at "totally" closed system anaesthesia were regarded as a
sporting pursuit of an eccentric minority. The reasons for these circumstances
were never explained precisely, often related vaguely to fears of failure in a
system dependent on relatively complex conduits, all valves which might fail.
Probably the most reasoned concern was that the practitioner was less sure of
the inspired gas concentrations than was the case in high flow systems, although
a 3 litre min-1 fresh gas supply to a circle will ensure that the fresh and
inspired gas concentrations are very nearly the same.
In parallel there has been concern about the stability of anaesthetics in
contact with soda lime (trichlorethylene, halothane etc), and the accumulation
of unwanted constituents of expired gas, notably carbon monoxide. The
justification of these concerns has usually been drawn from contrived
experimental designs or rare clinical cases. Additional factors against the
development of low flow practice have included concern about the environmental
risks of anaesthetic gases and vapours, uncertainty about the future role of
nitrous oxide and the intense promotion of intravenous methods of anaesthesia.
Today we have more than adequate reassurance from gas and vapour monitoring and
an increasing use of new expensive volatiles which can only be justified in a
low flow setting. The risks, if any, of instability of chemicals within the COs
absorption system appear to continue to be aired and need to be defined.
A final phobia relates to vaporisation within the breathing system. This also is
not new but reassurance on the safety of this desirable mode is still required.
The main lesson from the past is that practice truly based on scientific
evidence is often quite different from actual practice where fully developed
ideas, extrapolations or misunderstandings frequently prevail.
Should we return to Vaporizers in Circuit?
D.C.White
The use of vaporisers within circle systems (VIC) has been considered
unsatisfactory in the past because the concentration of anaesthetic agent within
the system is not known. This criticism also applies to the use of vaporisers
outside the system when the fresh gas flow rate (FGF) is low. However, in the
case of VOC, the agent concentration does not normally rise above that in the
FGF. With VIC the concentration can, under certain circumstances, rise to high
levels.
The availability of agent monitors has changed this situation. Not only can VIC
be safely used but studies can be carried out which analyse performance and show
certain advantages of the technique.
The vaporisers are small, cheap, versatile (not agent specific) and do not need
maintenance. The absence of temperature compensation appears a drawback but in
practice the fall in delivered concentration which occurs in the first twenty
minutes of use, matches in time course the decreasing requirement of agent as
the lungs and vessel-rich group of organs come into equilibrium with the
inspired concentration. After this time a temperature equilibrium occurs which
depends on the vaporiser setting.
If the patient is breathing spontaneously there is a safeguard against overdose
which
produces respiratory depression. This reduces gas flow through the vaporiser and
the inspired concentration falls. Conversely, if anaesthesia is light, surgical
stimulus causes respiratory stimulation, the inspired concentration rises and
anaesthesia is deepened.
During controlled ventilation, if the system is completely closed (FGF = basal
oxygen) then the agent concentration rises steadily. However, if the FGF is
increased above basal there is a leak out from the system which tends to
stabilise the concentration. This occurs at a FGF of about IL/min. Above this
FGF, if the vaporiser setting is unchanged, the agent concentration is regulated
by the FGF. The higher the FGF the greater is the leak from the system and the
lower is the agent concentration. In clinical practice the system operated in
this manner is stable and easy to control.
Data to support the statements made in this summary will be presented.
Sevoflurane was first synthesized in 1968, Early animal work and the first
reports of the use of sevoflurane in human subjects were encouraging. However,
compared with other agents being investigated at that time sevoflurane is a
relatively unstable molecule. It undergoes both hepatic metabolism and is broken
down by soda lime. Further work on sevoflurane in the US was halted for
commercial and scientific reasons. Development continued in Japan where it was
released in 1990.
SEVOFLURANE ANAESTHESIA IN LOW-FLOW SYSTEMS
Michael Nathanson,
Nottingham.
Sevoflurane has good reasons to commend its use in a circle system at low flows
- its low blood gas partition coefficient ensures that depth of anaesthesia can
be precisely controlled even at low fresh gas flows and it is expensive to use
at high fresh gas flows.
Approximately 5% of administered sevoflurane undergoes hepatic metabolism to
inorganic fluoride ions and hexafluoroisopropanol. Although
hexafluoroisopropanol is potentially hepatotoxic it is conjugated so rapidly
that liver damage seems theoretically impossible. Despite several studies
showing that peak serum fluoride concentrations after sevoflurane anaesthesia
can be in excess of 50 umon/1, there is no data to show that these levels of
inorganic fluoride are detrimental either to patients with normal renal function
or to those
with renal failure. Serum fluoride levels are not related to fresh gas flow
rate.
Sevoflurane reacts with the strong bases in carbon dioxide adsorbents to form
fluoromethyl-2,2-difluoro-l-Ctrifluoromethyl) vinyl ether, otherwise known as
Compound A. Although five breakdown products may be formed experimentally only
Compounds A and B have been found in anaesthesia circuits.
Compound A has been measured in the inspiratory limb of anaesthetic circle
systems under a variety of conditions. The mean peak concentration ranged from
2.1 to 32.0 ppm. The maximum individual peak Compound A concentration detected
was 60.8 ppm. The factors thought to affect the concentration of sevoflurane
degradation products include: temperature of the carbon dioxide absorbent, fresh
gas flow, patient's carbon dioxide elimination, concentration of sevoflurane in
the circle system, type of absorbent used, freshness of the absorbent, and water
content of the absorbent. In particular higher fresh gas flow rates are
associated with decreased concentrations of Compound A, as are reductions in
temperature of the absorbent.
Compound A toxicity in rats is both concentration and time-dependent. The
concentration of Compound A required to kill 50% of rats (L50) after a 1 h
exposure is approximately 1050 ppm, and after a 3 h exposure is 400 ppm. Acute
toxicity primarily involves pulmonary and renal damage, Exposure to Compound B
at 2,400 ppm for 3 h is not toxic to rats. The threshold level of Compound A to
produce renal damage in rats is 150-200 ppm for a 1 h exposure and 50 ppm for a
3 h exposure. The pattern of renal injury seen is a corticomedullary proximal
tubular necrosis.
The exact mechanism of Compound A toxicity in rats is unknown. However, Compound
A is conjugated in the liver, the conjugate then passes to the kidney where it
undergoes a ?-lyase reaction to form potentially nephrotoxic acylating
intermediates. The activity of P-lyase in the human kidney is 10% of the
activity seen in the rat kidney. If the same pathways exist in humans, this
difference in enzyme activity may explain the apparent lack of toxicity of
Compound A so far seen in human studies and in clinical use.
A number of groups have looked for evidence of renal or hepatic dysfunction
after sevoflurane anaesthesia in a circle system. Although minor changes in some
laboratory tests have been seen (for example, rises in bilirubin, AST and ALT),
these were clinically insignificant and overall there was no indication of organ
toxicity. Furthermore such changes can be seen after anaesthesia with halothane,
enflurane and isoflurane. However, routine laboratory tests may be insensitive
to mild degrees of organ impairment and more detailed studies are required to
confirm these findings.
Molecular sieves may be used as an alternative to carbon dioxide absorbents
containing strong bases. Breakdown of sevoflurane does not occur and Compound A
concentrations do not rise above baseline (contaminant) levels.
Anaesthetic agents which contain the CF,H- group can react with carbon dioxide
absorbent to form carbon monoxide under certain conditions. This group is not
present in sevoflurane, Even under extreme conditions of completely dry
absorbent and high temperatures, carbon monoxide formation during use of
sevoflurane is negligible.
In conclusion, sevoflurane does offer a significant advance over previously
available agents and appears to be suitable for use in low flow systems.
Although the degradation of sevoflurane in low flow systems is a cause for
concern, no toxicity has been detected in man. However, during clinical use
Compound A concentrations do approach levels found to be nephrotoxic in rats and
further work including sensitive tests of renal and hepatic function are
required. The use of molecular sieves may offer an acceptable alternative to
soda lime in the future.
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