Department of Environmental and Occupational Medicine, University of Aberdeen, University Medical School, Foresterhill, Aberdeen AB25 2ZD, UK j.a.ross@abdn.ac.uk
Declaration of interest. Patented by Aberdeen University. If commercial production were to occur, the university and the authors would benefit.
Accepted for publication: July 18, 2002
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Abstract |
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Methods. Possible phase separation of this mixture was studied by analysis of samples from pre-filled cylinders as they were cooled.
Results. Condensation of isoflurane was found at 3.1°C in a cylinder, which held 8.7 MPa at 15°C. In a cylinder holding 13.8 MPa, which is the standard filling pressure stipulated by the National Health Service, the condensation temperature was 2.3°C. At the highest cylinder filling pressure investigated (14.15 MPa) the separation temperature was even less, 3.0°C. After exposure of cylinders to 40°C and complete phase separation of the mixture, complete mixing was achieved by 24 h storage in the horizontal position at room temperature and, either three complete inversions of the cylinder or mechanical rolling at 30 r.p.m.
Conclusions. These findings should assist the use and storage of IN2O.
Br J Anaesth 2002; 89: 81419
Keywords: anaesthetics volatile, isoflurane; anaesthetic gases, nitrous oxide; anaesthetics, gases, premixed gases
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Introduction |
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Methods |
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Sampling tubes were attached to the cylinder head needle valves and a thermostatically controlled water circulator (Grant FH15) circulated warmed anti-freeze solution through plastic tubing coiled around the valves and attached tubing in order to prevent condensation of the test mixture after it had been sampled from the cylinder. After the warming coils were applied, the sampling arms were insulated with several layers of reflective plastic foil.
The test cylinder was cooled in a deep freeze chest (Derby), rated to operate at 40°C, within which an electric fan was used to circulate the air and a heat gun was used to slow cooling if it became too rapid. Three thermistor probes (Yellow Springs Instruments series 400) were calibrated against a mercury thermometer (National Physical Laboratory) and used for temperature recording. One was placed on the external surface of the cylinder half way along its length. It was shielded with a block of polystyrene foam backed with a 9 cm diameter pad of closed cell 4-mm-thick neoprene foam. Two more temperature probes were placed within the freezer cabinet for observing the circulating air temperature both close to floor and at close to lid levels.
Three series of experiments were performed. Before each, the test cylinder was filled as described above and then lowered into the deep freeze. The lid was closed on top of the wires and tubes trailing over the edge, and continuous gas sampling was commenced in anticipation of the changes in isoflurane concentration. Gas flow from the sampling arms was checked at intervals and the metering valves were adjusted to allow a flow of approximately 1 g of IN2O per minute using a specially marked flow meter. The gas sampled was analysed with an infra-red analyser (Datex Normac AA-102) for isoflurane and a paramagnetic analyser (Servomex type 570A/580A) for oxygen. Output signals from the analysers and thermistors were recorded on a flat bed recorder (Rikandenki RO3).
The temperature of the cylinder was allowed to decrease until a change in the concentration of isoflurane measured indicated the start of separation of the gas mixture. The first formation of isoflurane dew was taken to occur as soon as the concentration of isoflurane in the bottom sample began to decrease (Fig. 2). It was assumed that this was caused by isoflurane being lost as dew from the gas flow entering the dip tube becoming attached to immediately adjacent cold surfaces. The next stage is the formation of heavy vapour in the bottom part of the cylinder. As this happens, the concentration of isoflurane in the bottom sample increases and the concentration in the top sample decreases. The first formation of heavy vapour was noted when the decrease in isoflurane concentration stopped and a sustained increase had started (Fig. 2). The final stage is the formation of a pool of isoflurane liquid in the bottom of the cylinder. This contaminates the sampling system with large quantities of liquid isoflurane, which are then difficult to get rid of, so cooling was not allowed to progress to this stage. The valve on the sample path was closed and cooling stopped when the isoflurane concentration had increased to more than 0.3% and before liquid isoflurane had formed in the bottom of the cylinder.
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Remixing cylinder contents after their separation as a result of cooling
Two 12.2-litre capacity cylinders were used. They were filled with 54 g isoflurane and 4001 g EntonoxTM to give a homogenous concentration of 0.25% isoflurane and then cooled to 40°C in a deep freeze chest for at least 24 h. This causes separation of isoflurane and nitrous oxide to form a pool of liquid in the dependent portion of the cylinder. The cylinders were then removed and stored either in the vertical or horizontal position for some time at room temperature before being checked. Mixing of cylinder contents was then attempted either by three complete inversions of the cylinder or by rolling the cylinder at 30 r.p.m. for 5 min. The contents of the cylinder were regarded as homogenous when the concentration delivered was unchanged by inverting the cylinder. Thermistor probes were attached to the cylinder surface at its mid-point in order to detect the temperature fall during inversion, which would be caused by the partial re-vaporization of agitated liquid contents. Gas analysis with the cylinder inverted was not carried out if there was free liquid in the cylinder. The cylinder contents were then mixed by either rolling at 30 r.p.m. or by repeated inversions. Each cylinder was used in each of the four test conditions.
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Results |
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Discussion |
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Two effects explain this behaviour. The application of pressure to the condensed phase of a substance causes its vapour pressure to rise. This effect was first described by Poynting and is named after him.10 In addition, gas phase molecules attract molecules out of the condensed phase by the process of gas solvation.11 In high-pressure gaseous mixtures it is correct to think of the components as dissolved in each other. We studied the relative contribution of solvation and the Poynting effect in mixtures of isoflurane and 50% nitrous oxide in oxygen. At 10 MPa and 20°C the saturated vapour pressure of isoflurane was 95 kPa, an increase of 63 kPa from the saturated vapour pressure at atmospheric pressure.6 The Poynting effect predicted an increase in vapour pressure of 22 kPa at this pressure and so an increase of 41 kPa could be attributed to gas solvation. The solvent property of a gas depends on its density, which increases with pressure and so higher cylinder pressures are associated with greater solvent power of the gas. However, the increase in solvent power of the gas phase may not be enough to prevent condensation if a fixed concentration is studied and at pressures up to 9.35 MPa 0.25% isoflurane becomes progressively less thermally stable. At higher pressures, however, there is a progressive improvement in stability indicating that the solvent capacity of the gas mixture increases.
Although the phase behaviour of multiple component gas mixtures can be estimated by modelling techniques we have found it easier and more direct to adopt an experimental approach.6 7 This study has partially defined the phase diagram for the behaviour of 0.25% isoflurane in a mixture with equal parts of nitrous oxide and oxygen. A phase diagram is a map of the ranges of pressure and temperature at which each phase of a substance is the most stable (that is, has the lowest Gibbs energy).11 The cricondentherm is the maximum temperature of a multi-component system at which liquid and vapour can exist in equilibrium, and above which liquid cannot be formed regardless of pressure. The cricondenbar is the maximum pressure at which liquid and vapour can co-exist.12 At a temperature above its cricondentherm or at a pressure above its cricondenbar a mixture must be in a homogeneous phase.
We have defined the cricondentherm of IN2O as 3.1°C. Importantly, we have shown that this occurs at a pressure typical of a cylinder that is between one-half and two-thirds full (assuming a usual cylinder pressure for medical gas of 13.8 MPa). The temperature at which separation will start to occur in a full cylinder is 2.3°C. In other words the contents of a full cylinder are more stable with respect to temperature than of one that is partially used. This has important implications for the transport, storage and use of IN2O. An ambient outside temperature of 2.3°C is not unusual in the UK and so storage or transport in unheated areas would have to be avoided. An alternative approach might be to increase the cylinder filling pressure for the mixture, as this would make it more stable. Once the cylinder is in use, the thermal stability decreases until the cylinder pressure reaches 8.7 MPa. Further use improves stability again. Once a cylinder is in use it should be kept where ambient temperature cannot fall below 3.1°C. The freezing and recovery experiments show that the separated premixed gases are stable and that mechanical mixing after re-warming is necessary. It is better to store cylinders in the horizontal position.
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References |
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