Simulated use of premixed 0.25% isoflurane in 50% nitrous oxide and 50% oxygen{dagger}

J. A. Ross* and M. E. Tunstall

Department of Environmental and Occupational Medicine, University of Aberdeen, University Medical School, Foresterhill, Aberdeen AB25 2ZD, UK j.a.ross@abdn.ac.uk


{dagger}Declaration of interest. Patented by the University of Aberdeen. If commercial production were to occur, the university and authors would benefit.

Accepted for publication: July 18, 2002


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Isoflurane (0.25%) in premixed nitrous oxide and oxygen, 50/50, v/v (IN2O), has been suggested for pain relief in labour. Possible phase separation of the mixture was studied during simulated administration.

Methods. A sinusoidal pump set at stroke volume of 2 litres and a rate of 20–22 bpm and cycling for 1 min in three was used to simulate breathing during the painful contractions of labour.

Results. The temperature inside a 10-litre capacity cylinder did not drecrease sufficiently to cause separation of the gas mixture. Temperature in the demand valve decreased to –15.5°C and this caused a small amount of liquid formation within the valve. Accordingly, the inspired concentration during the first breath of mixture in a cycle could be transiently as high as 0.55%. The concentration observed at the patient connection after the first breath varied between 0.17 and 0.28%.

Conclusions. The system delivered a clinically acceptable performance although further development to avoid liquid condensation is needed.

Br J Anaesth 2002; 89: 820–4

Keywords: anaesthetics volatile, isoflurane; anaesthetics gases, nitrous oxide; anaesthetics, gases, premixed gases


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The addition of 0.2–0.25% isoflurane to premixed nitrous oxide and oxygen, 50/50, v/v (IN2O), is helpful for the relief of pain in labour1 2 and for the removal of chest drains.3 Isoflurane and the proprietary preparation of 50% nitrous oxide in oxygen (EntonoxTM) can be premixed together in the same storage cylinder at economical filling pressures.4 Premixed anaesthetic agents and oxygen, stored under pressure in a single cylinder, allows simple administra tion of a fixed dose of agent, but temperature reduction in the demand valve and in the cylinder during use may cause phase separation. Rapid removal of gas from a high-pressure cylinder causes cooling which can cause frosting of the cylinder and attached equipment. For IN2O, if the temperature in a cylinder decreased below the separation temperature during use, it would become unsafe. Similarly, if the temperature of the delivery valve decreased below the separation temperature, then the volatile agent would condense and the characteristics of the mixture delivered might change. We studied how a full cylinder of IN2O gas cools during simulated use and the concentration of isoflurane delivered.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Simulated use experiments
Isoflurane concentration and temperature in the administration set
A chrome molybdenum steel cylinder of nominal 12.2-litre water capacity rated to a working pressure of 20.7 MPa gauge (Faber, British Standard 5045) was used. The cylinder was filled with 4046 g (14.30 MPa at 15°C) of 0.24% isoflurane in a proprietary mixture of 50% nitrous oxide in oxygen (EntonoxTM, BOC Ltd) and fitted with a demand valve and administration set (Ohmeda). The patient connection of the breathing set was attached to the bag of a 5-litre ‘bag in bottle’ system with one-way valves attached to form as a patient simulator. The bottle was connected to a sinusoidal pump (P.K. Morgan Ltd. DEV2). The breathing set used was of the standard type of corrugated black rubber fitted with an elbow connector (22 mm ID taper) at one end for connecting to a demand regulator, and an EntonoxTM hand-piece (22 mm OD taper) at the other end. The hose was 1.5 m in length with an internal volume of approximately 750 ml (Fig. 1).



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Fig 1 Variable scale broken diagram of breathing circuit and patient simulator. A and B, inserted gas sampling tubes; C and D, inserted thermistor probes within the EntonoxTM breathing hose. V, position of demand regulator (EntonoxTM valve) connecting gas cylinder to hose; P1, patient end of breathing hose; P2, connection point of patient end to ‘bag-in-bottle’ with uni-directional valves shown; E, closed off expiratory cap on EntonoxTM hand-piece; F, connection to sinusoidal pump for actuating the ‘bag-in-bottle’ (patient simulator).

 
The volume of the IN2O gas mixture pumped out of the exhalation port of the patient simulator was measured by a dry gas meter (Harvard) before being dumped through a passive scavenging system. The gas samples were analysed with an infra-red analyser (Datex Normac AA-102) for isoflurane and a paramagnetic analyser (Servomex type 570A/580A) for oxygen. Nitrous oxide concentration was calculated by the difference. Output signals from the analysers and thermistors were recorded on flat bed recorders (Rikandenki RO2 and RO3). Data points were taken from the recording paper. The recording pen was set at a gain of 25 mm per 0.1% isoflurane or per 5°C.

Gas was sampled for analysis at both ends of the breathing hose and temperature in the gas flow was measured by thermistors at the same points. A third thermistor probe was placed on the surface of the cylinder at its mid-point and was shrouded by a block of polystyrene covered in turn by a 5 cm diameter patch of 4 mm closed cell neoprene. A fourth probe recorded the room temperature at workbench level. All thermistor probes (Yellow Springs Instruments series 400) were calibrated against a mercury thermometer (National Physical Laboratory). Gas sampling was intermittently switched between the ‘patient end’ (hand-piece), and the ‘valve end’ (elbow connector). The sinusoidal pump was set to a tidal volume of 2 litres and a rate of 21 strokes min–1 and switched on for 1 min and off for 2 min by an automatic timer until the cylinder was empty. The experiment was conducted after the 12-litre cylinder had stood overnight and its external temperature was 20°C.

Internal cylinder temperature and isoflurane concentration
We used a 10-litre test cylinder, fitted with dip-tubes, as described previously.4 It contained 3528 g (14.20 MPa at 15°C) IN2O gas (containing 0.25% isoflurane). It was attached to the patient simulator via the EntonoxTM demand regulator and breathing hose and emptied by the sinusoidal pump as described above for the 12.2-litre cylinder, but at 22 strokes min–1. The cylinder and its appendages rested on electronic weighing scales (Sartorius IB 31000P) and the weight of the cylinder assembly and the volume of expired gas were recorded for each 3-min cycle. Internal and external cylinder temperatures were continuously recorded.

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 in a 4.72 mm internal diameter dip tube with a closed end that reached to 6.5 mm above the cylinder bottom. This measured the gas temperature internally in the most dependent part of the cylinder. Another 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. The remaining sensor was used to measure room temperature.

Minimum temperatures, at the end of each cycle, were measured from the recording chart. The isoflurane concentration was continuously recorded alternately, from the distal (patient) end of the breathing hose and from inside the bottom of the cylinder via the long dip-tube.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Isoflurane concentration and temperature in the administration set
Isoflurane concentration at the demand valve
The duration of the experiment was 201 min and measured pump output was 2797 litres. During the 1 min of breathing ‘on’ phase of the 3 min pump cycle, the temperature in the gas flow at the valve end of the hose decreased, the minimum temperature reached being –15°C (Fig. 2). The temperature at the patient end of the hose did not decrease below 15.3°C. Temperature changes at the patient end were minimal, the maximum change being 0.7°C. Values of the lowest temperature in each cycle are plotted (Fig. 2). The decrease of temperature in the demand valve caused condensation of isoflurane on cold surfaces so that during the 2 min ‘breathing off’ cycle, as the valve temperature increased, condensate evaporated causing an increase in concentration to a plateau level which did not exceed 0.55% and decreased during the experiment. This concentration decreased abruptly at the commencement of the first inspiration and was followed by a fluctuating pattern of isoflurane concentration during the 1 min ‘breathing on’ period (Fig. 3).



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Fig 2 Temperature changes at the valve end of the breathing hose during the ‘breathing on’ cycle, and the temperature changes on the surface of the middle of the cylinder. Only the lower temperature of the minimal temperature swings at the patient end of the hose are plotted.

 


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Fig 3 Isoflurane vapour concentrations at the valve and the patient ends of the breathing hose at the beginning of a ‘breathing on’ cycle (20 pump strokes at 2 litres stroke–1).

 
Isoflurane concentrations at the patient connection
During the 2 min ‘breathing off’ cycle, continuous gas sampling showed a slight and gradual decrease of isoflurane concentration. This increased sharply to a peak at the start of the first inspiration, which was followed by a fluctuating pattern of isoflurane concentration during the 1 min ‘breathing on’ cycle (Fig. 3). The peaks of isoflurane vapour concentration at first inspiration at the patient end of the hose did not exceed 0.4%. However, analysis was alternated between the patient and valve end of the hose and greater concentrations could have been present. The fluctuating pattern had a minimum of 0.17% recorded at 12 min and a maximum of 0.28% recorded at 57 min into the experiment. The variation in delivered concentration of isoflurane was greatest when the cylinder was full and virtually ceased when the temperature at the valve end of the breathing hose decreased to less than 3°C at the end of each ‘breathing on’ period. The contents of the cylinder showed no difference in the concentration of isoflurane in the cylinder between a sample taken at the beginning and one taken at the end of the experiment, indicating that no condensation of isoflurane had occurred in the 12.2-litre cylinder during the experiment.

Simulated use experiments: measurement of internal temperature and isoflurane concentration during cylinder emptying experiment
The experiment was conducted after the special 10-litre cylinder had stood overnight and its internal temperature was 16.2°C. During the experiment, room temperature rose from 16.1°C to a maximum of 18.9°C. At the end of the experiment when the pump was labouring to obtain gas through the system the pump was switched off. There was sufficient residual pressure within the cylinder to release 7 litres of gas containing 0.25% isoflurane, confirming that there had been no change in the concentration of isoflurane within the cylinder from beginning to end. Excluding the residual 7 litres, the total expired gas volume was 2460 litres for 56 cycles of 3 min each, equivalent to 43.93 litres for every minute the pump was on, representing constant emptying rate of 14.64 litres min–1. The rate of cylinder emptying was linear as was the weight reduction of the cylinder contents, and was not affected by the marked frosting of the demand regulator, which occurred during the first half of the experiment. From the twelfth cycle onwards, the falling internal temperature curve from the experiment is shown with the dew curve4 in Figure 4. It shows that the temperature fall during the experiment did not reach any point where phase separation could occur. This was confirmed by the consistency of the isoflurane sampling record throughout the experiment, both from the patient end of the breathing hose and from the bottom of the cylinder via the long dip tube. The concentration of isoflurane was 0.25% in the cylinder gas both at the start and at the end of the experiment.



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Fig 4 The cooling curve of the temperature (recorded internally at the bottom of the 10-litre cylinder), in the emptying experiment superimposed on the dew curve for IN2O (the temperature in the cylinder at which isoflurane starts to condense).4

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We measured aspects of the performance of IN2O delivery using a sinusoidal pump stroke volume of 2 litres. The rate was 22 strokes min–1 for the special 10-litre cylinder. The peak inspired flow to the pump was therefore 138 litres min–1. An on–off cycle of 1 min on and 2 min off was chosen. The total volume of gas used was 2460 litres over a period of 168 min. These values were chosen to model the breathing pattern seen in the second stage of labour. Measurements have shown a peak inspiratory flow of 140.6 litres min–1, tidal volume of 866 ml and a ventilatory frequency of 20 breaths min–1, with contractions lasting 46 s with an interval between contractions of 2 min.5 The mean consumption of a 50% nitrous oxide in oxygen mixture during labour in primiparous mothers was 764 litres with a maximum of 2580 litres. A representative period of time over which gaseous analgesia was used was the last hours of first stage and a second stage of 30 min.5 Apart from peak inspiratory flow, therefore, the bench model exceeded mean values. In clinical use it would be unlikely that the model could be sustained for 168 min. If mean values for the use of 50% nitrous oxide are applied, the amount of gas used in the experiment would be typical of that used by three average primiparous mothers. In practice, therefore, the degree of cooling demonstrated during the bench experiments would be unusual.

We measured internal cylinder temperature during simulated use in order to see whether it would drop below the cricondentherm. (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.6 At a temperature above its cricondentherm or at a pressure above its cricondenbar a mixture must be in a homogenous phase.) This did not happen and there was no separation of the isoflurane component of the gas mixture. Accordingly, we did not expect separation of the mixture during clinical use and residual gas analysis of cylinders returned from clinical use confirmed this.

The temperature decrease in the cylinder depends on a number of factors. Gas expansion in the cylinder causes an adiabatic decrease in temperature that is related to the reduction in pressure. Gas expansion through the demand valve causes local cooling and heat will be lost from the cylinder contents into the metal so cooled. On the other hand heat passes into the cylinder contents from the cylinder itself initially and then from the environment through the cylinder wall to offset these two factors. The cylinder used for this experiment was 10 litres nominal water capacity. Clearly the temperature changes in either larger or smaller cylinders will be different. In larger cylinders, the rate of pressure decrease will be less although the heat lost through a cooling demand valve will be the same. The heat available from the metal of the cylinder and through the cylinder wall will be greater because of its larger mass and surface area. As temperature decrease is related to pressure decrease this will be less in a larger cylinder. The converse is true for small cylinders and if breathing volumes are kept the same, the temperature in a small cylinder will decrease much more than in a large cylinder. Therefore, although our experiment indicates that condensation of isoflurane in a 10-litre cylinder is very unlikely, the same may not be true for smaller cylinders and further study would be needed if such cylinders were to be used clinically.

Saturated vapour pressure is temperature dependent and during the simulated use experiments the airflow temperature dropped to –15°C at the demand valve end of the administration circuit. During the use of the proprietary mixture EntonoxTM the temperature of the demand valve may decrease to less than –20°C without affecting the function of the valve or the composition of the mixture delivered.7 At –15°C the saturated vapour pressure of isoflurane is 3.5 kPa and that of nitrous oxide is 2112 kPa.8 The pressure in the first stage of the demand valve is 1461 kPa and so the partial pressure of 0.25% isoflurane is 3.65 kPa and 50% nitrous oxide is 730.5 kPa. At temperatures of the order of –15°C and less, therefore, there is likely to be some condensation of isoflurane in the demand valve. Also, because of the much higher pressure, there is certain to be small amounts of both liquid nitrous oxide and isoflurane in the part of the regulator before the first stage valve. This explains the varying concentration of isoflurane observed in the breathing circuit. During each stroke of the pump, the temperature in the demand valve is reduced. Once the saturated vapour pressure becomes less than the partial pressure of isoflurane in the mixture, some condensation occurs on the cold surfaces of the demand valve. During the 2 min rest phase, the demand valve temperature rises and, as the condensate vaporizes, the concentration of isoflurane in the gas sampled by the analyser rises. However, the maximum concentration seen as a result of this effect was 0.55% at the valve end. The peak concentration seen at the patient end of the hose was transient and affected the first breath of a cycle only.

After the transient peak at the start of a breathing period, the concentration at the patient end of the hose varied between 0.17 and 0.28% and this is comparable with the performance of an Oxford Miniature Vaporiser under similar circumstances.1

While the variation in delivered concentration identified here has caused no problem in the clinical use of IN2O, the condensation of isoflurane that causes it is undesirable. Although the present system had an acceptable performance for clinical work, an administration system that prevents this effect would be desirable.

This agent, which has been suggested for use in pain relief in labour,9 may be criticised for causing local atmospheric contamination. Although not the topic of this paper, the practical use of such agents should consider environmental control. The United Kingdom Control of Substances Harmful to Health Regulations (1999) place a statutory obligation on the users of anaesthetics to control the exposure of hospital staff within occupational exposure limits and lower if this is practicable. The addition of isoflurane to premixed 50% nitrous oxide in oxygen makes atmosphere control even more necessary than with the use of nitrous oxide alone as there is a requirement to consider the additive effects of such agent mixtures. We found it was possible to collect the expired gas from the expiratory valve of the breathing apparatus in a simple and convenient way using the wall suction equipment.9 Other active scavenging systems would be as effective. In addition, our risk assessment of the use of the agent in a maternity suite did not reveal any problem before the clinical use of this agent.10


    Acknowledgement
 
We would like to thank Dr Vivek Kulkarni for constructing the special electronic timing device for us in the Department of Bio-Medical Physics and Bio-Engineering, University of Aberdeen.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Arora S, Tunstall M, Ross J. Self-administered mixture of Entonox and isoflurane in labour. Int J Obst Anesth 1992; 1: 199–202

2 Wee MYK, Hasan MA, Thomas TA. Isoflurane in labour. Anaesthesia 1993; 48: 369–372[ISI][Medline]

3 Bryden FMM, McFarlane H, Tunstall ME, Ross JAS. Isoflurane for removal of chest drains after cardiac surgery. Anaesthesia 1997; 52: 173–5[ISI][Medline]

4 Tunstall ME, Ross JA. Phase behaviour of premixed 0.25% isoflurane in 50% nitrous oxide and 50% oxygen. Br J Anaesth 2002; 89: 814–19[Abstract/Free Full Text]

5 Crawford JS, Tunstall ME. Notes on respiratory performance during labour. Br J Anaesth 1968; 40: 612–4[ISI][Medline]

6 Ahmed TH. Hydrocarbon phase behavior. In: Chilingar GV, ed. Contributions in Petroleum Geology and Engineering. Houston, Texas: Gulf Publishing Company, 1989; 7: 1–35

7 Hill DW. Pressure gauges and regulators. In: Hill DW, ed. Physics Applied to Anaesthesia. London: Butterworths, 1972; 47–69

8 Rodgers RC, Hill GE. Equations for vapour pressure versus temperature: derivation and use of the Antoine equation on a hand-held programmable calculator. Br J Anaesth 1978; 50: 415–24[Abstract]

9 Ross JAS, Tunstall ME, Campbell DM, Lemon JS. The use of 0.25% isoflurane premixed in 50% nitrous oxide and oxygen for pain relief in labour. Anaesthesia 1999; 54: 1166–72.[ISI][Medline]

10 Ross JAS. Isoflurane Entonox mixtures for pain relief during labour. Anaesthesia 2000; 55: 711–2[Medline]





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