1St Andrews Centre for Plastic Surgery and Burns, Broomfield Hospital, Chelmsford, Essex CM1 7ET, UK. 2Department of Anaesthesia, Imperial College School of Medicine, London, UK. 3Department of Anaesthesia, Northwick Park Hospital, London, UK*Corresponding author
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Accepted for publication: January 15, 2001
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Abstract |
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Br J Anaesth 2001; 86: 6459
Keywords: induction, anaesthesia; model, compartmental; anaesthetic techniques, inhalation; pharmacokinetics, isoflurane
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Introduction |
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The multi-compartment model has never been accepted universally,8 and recent work has been interpreted as evidence that anaesthetic uptake is constant after the first few minutes of inhalational anaesthesia.9 We have investigated this controversy by measuring the uptake of isoflurane during prolonged anaesthesia. We studied 20 patients undergoing reconstructive head and neck surgery using a computer-controlled closed anaesthetic breathing system into which isoflurane was injected to maintain a concentration of 1.3 MAC.
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Methods |
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Conduct of anaesthesia
After Ethics Committee approval and informed consent had been obtained, 20 patients undergoing head and neck surgery, were studied. A multi-disciplinary team of maxillo-facial, ENT, and plastic surgeons were involved to undertake these lengthy surgical procedures, some of which lasted up to 18 h. The surgery involved excision of tumour and reconstruction of the defect with a free tissue flap. The patients received oral temazepam premedication. Anaesthesia was induced with propofol 2.5 mg kg1 and fentanyl 4 µg kg1. A laryngeal mask airway (LMA) was then inserted, the patients were connected to a closed breathing system, and controlled ventilation was instituted. Liquid isoflurane was injected as described above to achieve and maintain an end-expired concentration of 1.5%. The airway was then secured by percutaneous dilatational tracheostomy. Atracurium (0.5 mg kg1) was used to facilitate insertion of the tracheostomy tube; no further dose of muscle relaxant was administered. The closed breathing system was then disconnected from the laryngeal mask and connected to the cuffed tracheostomy tube. Anaesthesia was continued with 1.5% end-expired isoflurane and an infusion of fentanyl at 05 µg kg1 h1. The end-expired carbon dioxide was maintained at 4.5 kPa.
Arterial and central venous catheters were placed using the radial artery and femoral vein respectively. ECG, arterial blood pressure, urine output, temperature (core and peripheral), haemoglobin and haematocrit, arterial blood acidbase status, fluid intake, and blood loss were monitored throughout. Temperature was maintained by surface warming (Bair Hugger, Eden Prairie, MN, USA). During the first 30 min of anaesthesia, it was occasionally necessary to treat hypotensive episodes with a 3-mg bolus of ephedrine. Thereafter, satisfactory blood pressure was maintained by infusion of i.v. fluid at 68 ml kg1 h1, using Hartmanns solution and Gelofusine (Braun, Melsungen, Germany) in a ratio of 4:1. Blood was given as required to maintain the haemoglobin concentration between 8 and 10 g dl1. In closed systems the inspired oxygen fraction (FIO2) reduces as nitrogen accumulates as a result of: (i) wash-out from the patient14 and (ii) the addition of air from the Capnomac oxygen reference flow, which is added to the sample return flow at a rate of 24 ml min1. FIO2 was maintained above 0.3 by intermittently venting the sample returned from the Capnomac so that oxygen entered the system from the gas piston. Any leak in the system revealed itself by an increase in FIO2 as oxygen from the gas piston replaced volume lost from the system.
Data analysis
The recorded rate of injection was normalized to 70 kg in proportion to each patients body weight. The patient results were too noisy to allow useful individual analysis. The parameters of the function Aiekit were adjusted to produce the best (i.e. least squares) simultaneous fit to the data, using an iterative technique on a spreadsheet (Solver, Microsoft Excel 97 SR-1). This function is the mathematical representation of exponential wash-in to multiple compartments. The significance of improvement in curve fit with increasing numbers of compartments was assessed using an F-ratio test.15 If these pharmacokinetic compartments are associated with the classical vessel rich, muscle and fat tissue groups, then compartment volumes and perfusions can be calculated. The amount of isoflurane in each compartment is given by integrating the appropriate term in the equation from zero to infinity. At 37°C the vapour volume of isoflurane is 207 times the liquid volume, and remembering that the equilibrium tissue concentration of isoflurane is 1.5
TG%, where
TG is the tissue:gas partition coefficient, we deduce that the volume of the ith compartment is 207 Ai/(0.015·ki·
TG) ml. The compartment perfusion is derived from the rate constant: ki=q
BG/
TG, where
BG is the blood:gas partition coefficient for isoflurane and q is the perfusion in units of ml blood (ml tissue)1 min1 (see Table 2 for the values of partition coefficient used).
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Results |
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Discussion |
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Uptake by the patient does not necessarily imply accumulation within the body. Losses of anaesthetic by diffusion through skin,16 mucous membrane, from wounds,17 urine, and metabolism18 should be insignificant. Assuming the solubilities of isoflurane in urine and saline are the same, the loss is approximately 9 ml of isoflurane vapour per litre of urine, or 0.5 µl min1 liquid isoflurane for our patients. The isoflurane content of the blood loss would have been an order of magnitude less. We are aware of only one mechanism by which our results could underestimate uptake. Methane can accumulate in closed breathing systems and has been reported to cause a gas analyser such as ours to read 0.79% halothane spuriously during total i.v. anaesthesia.19 The gain used in the infra-red system is less when isoflurane is selected and so methane would cause a lesser reading of 0.13% with isoflurane.20 That could mean that we were maintaining only 1.37% isoflurane (the remainder of the 1.5% being a spurious contribution from methane), resulting in a 9% underestimate of anaesthetic uptake at a true 1.5% concentration.
Airway manipulation and temporary disconnections of the breathing system resulted in very noisy data sets, especially during the first 30 min of anaesthesia. It is surprising that the mean uptake figures during this period have such plausible values. These noisy data detract less from the accuracy of our uptake measurements later in the anaesthetic, which was the main focus of this study.
Our results show that anaesthetic uptake continues to reduce for 10 h. That may seem to run counter to a recent statement by Hendrickx and co-workers that uptake becomes effectively constant after a 4 min wash-in period.9 Lin too has claimed that uptake is constant.8 There are three reasons that make this contradiction more apparent than real. First, we agree with the editorial21 accompanying Hendrickxs work that his results show uptake reducing throughout the first 49 min, not constant from 4 min. Second, we have presented our results in terms of rate of uptake, not cumulative uptake. The small, continued reduction in rate of uptake would indeed become almost negligible when viewed atop the accumulated load of isoflurane. Finally, we have been careful to keep our breathing system as near completely closed as possible. A small but constant leak, as might occur in routine use, would require an increase in anaesthetic delivery to counter it, so the reduction in anaesthetic uptake would be a smaller part of the rate of anaesthetic use and therefore less easy to discern. Thus, although we can agree that, for clinical purposes, isoflurane uptake becomes almost constant after a period of wash-in, uptake actually continues to reduce over a period of at least 10 h. Our results are compatible with the conventional perfusion-limited model of anaesthetic uptake and distribution.
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References |
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