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XENON was discovered in 1898 and first used as an anesthetic in 1951. 1It is more potent than nitrous oxide (N2O) with a minimum alveolar concentration (MAC) of approximately 71%, and its low blood-gas partition coefficient of 0.14 (recently recalculated as 0.115) results in rapid induction and recovery. 2–7Interest in xenon is high because of medical and environmental concerns about N2O; however, use may be constrained high cost. 8–10Fully closed rebreathing circuits are one method of minimizing costs. It is possible to close a conventional circle system, with the anesthesiologist varying the fresh gas flow to match uptake via the lungs. However, better control might be achieved by automation of this procedure. 8–11We describe a closed breathing system that may have advantages versus other designs.
Materials and Methods
The breathing system comprised a disposable carbon dioxide absorber–valve unit (King Systems Corp., Noblesville, IN) plus hoses; a mechanical ventilator (Kontron ABT 4000, Milan, Italy) and a bellows system modified by one of the authors (J. D.) to allow oxygen entry into the circle (fig. 1). At equilibrium, oxygen was added automatically at end-inspiration to keep the volume constant, replacing gas uptake from the closed circle. The system volume was approximately 2,170 ml (770 ml circle volume + 900 ml functional residual capacity + 500 ml tidal volume delivered).
With a xenon–oxygen mixture in the circle, this mechanical arrangement would result in a gradual increase in circle oxygen concentration as uptake of both gases was replaced with oxygen. This tendency was offset by delivery of xenon boluses to the circle via a computer-controlled magnetic valve (Airmatic-Allied Inc., Wilmington, OH), to maintain a stable measured oxygen concentration. The computer control algorithm was written using Labview software (National Instruments, Austin, TX) and based on the algorithm of Luttropp et al . 8It was a model-based, forward-feedback loop-control system in which a volume of xenon was delivered to an estimated distribution volume to achieve a target measured oxygen concentration by dilution. The estimated distribution volume comprimised the volumes of the breathing system and lungs plus a volume representing the continual loss of gas by tissue uptake. Initial xenon overdose to the circle while the algorithm optimized an appropriate distribution volume was prevented by use of a deliberately low 2-l starting value. The computer controlled and recorded xenon bolus volumes by varying the magnetic valve opening time; the flow rate through the valve was constant and known. The condition for xenon delivery was oxygen concentration greater than target value and bellows nearly empty (oxygen about to be added) and previous delivery at 60 s or more (to allow mixing of previous xenon bolus). When running closed, the bellows never filled completely, and, thus, no gas was spilled. Xenon was delivered to the expiratory limb to maximize mixing before it entered the lungs. Leak testing was performed via ventilation of a dummy lung. Absence of movement of the oxygen flow indicator confirmed a lack of volume loss. A small leak across the automatic oxygen addition valve mechanism could theoretically be tolerated as any leaked gas would be flushed back by oxygen during the following cycle.
Anesthesia and Surgical Preparation
Experiments were performed in five purebred, large, white male pigs. All complied with the 1986 Animals (Scientific Procedures) Act of the United Kingdom in accordance with the National Institutes of Health guidelines on the use of experimental animals. Anesthesia was induced using a halothane–oxygen–nitrous oxide mixture, and the trachea intubated with use of an uncut 6.5-mm ID cuffed tube (SIMS Portex Ltd., Hythe, UK) without neuromuscular blockade. After right external jugular vein cannulation, anesthesia was maintained with an alphaxalone–alphadolone infusion at 15 mg·kg-1·h-1, and mechanical ventilation continued with use of a 30% oxygen–70% nitrogen mixture.
The volume of each xenon bolus (V1) stored in the computer database was given by the equation
Summation of all values of V1gives the total xenon volume used at ambient temperature and pressure as estimated by the computer (Vc). Weighing of the xenon cylinder before and after each experiment allowed a more accurate calculation of the total volume used (Vw). Small errors in the values of V1as a result of the opening and closing times of the magnetic valve could be reduced by multiplying each by a correction factor defined as Vw/Vc.
A Servomex 570A paramagnetic oxygen analyzer (Servomex Ltd., Crowborough, Sussex, UK) was used to measure the circle oxygen concentration and data was recorded and continuously fed to the control algorithm. Xenon concentration was simultaneously measured using a calibrated Minison ultrasonic analyzer (Thomas Swan and Co., Ltd., Cambridge, UK). The sample gas was dried via passage through a 10-ml container of silica gel desiccant beads upstream of the analyzers, to reduce xenon measurement error, and returned to the circle otherwise unchanged.
A standardized 30-min nitrogen washout maneuver was performed using a Mapleson D system and a mechanical ventilator with a fresh gas flow of 10 l/min, set at 14 breaths/min, and a tidal volume varied to maintain a constant partial pressure of arterial carbon dioxide (Paco2). The closed breathing system, which was primed with oxygen, then was connected. The oxygen concentration was reduced to 80, 60, 40, and then 30%, with two cycles of the algorithm permitted at each of these steps for the algorithm to optimize the estimated xenon distribution volume (1 min/cycle). The final 30% oxygen target remained unaltered for the remainder of the experiment, which lasted 2 h in all five animals but was extended to a total of 4 h in one animal. Nitrogen concentration was measured intermittently using a mass spectrometer (model SX200; VG Quadropoles Ltd., Middlewich, Chesire, UK). Values are expressed as the median and range.
The weight of the pigs was 33 kg (range, 32–39 kg). The median volume of xenon used for the 2-h administration periods (at 22°C and atmospheric pressure) was 7.9 l (range, 7.4–9.1 l). In the 4-h administration, for a 33-kg pig, this volume was 13.1 l (table 1). More than half the xenon necessary for 2 h administration was used in the first 30 min.
An example of the performance of the system during a 2-h period is shown graphically in figure 2.
By the 90- to 120-min measurement interval, the median xenon volume necessary decreased to 1 l every 30 min, and in the pig that received xenon for 4 h, xenon expenditure continued at a similar rate.
Each time a new lower target oxygen concentration was set, the xenon concentration increased in a stepwise fashion, stabilizing within three cycles of the algorithm and within 5 min. The median nitrogen concentration in the breathing system after 2 h was 9.4% (range, 9–11.6%) and was 14.5% after 4 h.
The system functioned as intended. We performed a computer simulation using the NARKUP 4.11 program (Drs. D. C. White and G. G. Lockwood, Northwick Park Hospital, Harrow, UK), which uses a xenon blood-gas partition coefficient of 0.14. The simulated xenon expenditure for our system was 4.9 l after 2 h. 12The observed median xenon expenditure of 7.9 l after 2 h is good compared to the “ideal” value and is similar to the 7.6 l observed by Luttropp et al ., who used a functionally closed exchanger system in pigs of similar weight. 8In engineering terms, our breathing system should be closed, with zero gas loss; however this is difficult to achieve in practice. Our dynamic leak test relied on a rotating vane to show leaks. These have inertia and friction; therefore, a slight leak might be missed. A static leak test also would have been advisable. Xenon diffuses well through certain materials, for example, silicone rubber. Luttropp et al . Showed a loss of 1.5 l via silicone hoses over 2 h in similar experiments. 8In the current study, the hoses, the gas sampling, and the return lines were made of polyethylene, through which xenon diffuses poorly, and the xenon analyzer contained stainless steel tubing. However, a latex rubber bellows was used because polyethylene was unavailable, endotracheal tubes and cuffs were made of silicone rubber, and the oxygen analyzer internal hoses were made of synthetic rubber. These were potential routes of xenon loss.
With closed systems, accumulation of gases such as nitrogen and methane can dilute the delivered xenon concentration. A denitrogenation period is necessary if 1 MAC of xenon is to be delivered (71%) because flushing the circle to remove nitrogen is extremely expensive. Measured nitrogen concentrations were approximately 10% after 2 h despite denitrogenation; therefore, this problem is clinically relevant. If xenon use were balanced by adjunctive agents, as in conventional anesthetic practice, modest xenon dilution by nitrogen could be tolerated. Suitable adjuncts include opioids and very-low-dose propofol target-controlled infusion. These have been used clinically by other groups (personal verbal communication, Priv. Doz. Dr. Thomas Marx, M.D., Xenon Group, University of Ulm, Germany, September 3, 1999).
In summary, we described a closed anesthesia system that could also be used as part of a conventional anesthesia circle system. We demonstrated that it could successfully and economically deliver a 70% xenon–30% oxygen mixture for up to 4 h in a pig model. With appropriate safety devices, this system could be developed as a practical closed anesthesia system using xenon alone or in conjunction with volatile or intravenous agents.
The authors thank Evelyn Shervington, M.A., Geoffrey Lloyd, Ph.D., and Michael Garrett, B.Sc., British Oxygen Company (BOC) Europe, Guildford, England, United Kingdom, for technical advice, equipment, and supply of xenon gas; Alan Green, B.Sc., and Ian Revell, Penlon Ltd., Abingdon, Oxford, United Kingdom; Andrew Norman, Respiratory and Anaesthetic Support Services, Cardiff, Wales, United Kingdom, for items of equipment; Rod Mason, Ph.D., Lecturer, Department of Physical Chemistry, University College Swansea, Wales, United Kingdom, for analyses of gas samples by mass spectrometry; and Tzveta Ivanova-Stoilova, M.D., Ph.D., F.R.C.A., Royal Gwent Hospital, Newport, Wales, United Kingdom, for translation of Russian references.