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Response to A Farmery's e-letter
- Giles R Nordmann, Peter Stoddart and Andrew Wolf (15 September 2006)
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Exposure-time sensitivity of emergence following volatile anaesthesia
- Andrew D Farmery (9 June 2006)
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Giles R Nordmann , Peter Stoddart and Andrew Wolf
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Editor – We would like to thank Dr Farmery for his interest in our study. We recognise that linear regression analysis assumes the data is Gaussian and is not particularly appropriate for non-parametric data. We therefore did not carry out any further statistical tests from Figs 4 and 5 or refer to them with a view to statement justification. All statistical tests were non-parametric and are summarised in the second paragraph of the Results section. From this data we can see firstly that times to reach recovery milestones for all age groups were similar for desflurane. Although a significant difference was discovered in these milestones between desflurane and isoflurane for both age groups the younger patients (<4yr) had markedly lower median times to all recovery milestones. It is from this we observed that the younger children seemed to be less susceptible to delayed emergence from isoflurane compared to older children. We think Dr Farmery’s further suggestions as to the possible physiological and pharmacological mechanisms involved in explaining the reduced time effects of isoflurane on emergence from anaesthesia in younger children are helpful. Our view , based on the known age related differences in physiology is that faster wake up is primarily related to younger children having a higher alveolar volume:FRC ratio, a larger cardiac index and a greater relative blood flow to the brain in the younger age group. These features will all act to speed both onset of anaesthesia and emergence. We are in total agreement that the lack of lipid solubility of desflurane is the dominant factor for its more rapid emergence and recovery characteristics. Our data supports the theoretical basis that the physiochemical characteristics of desflurane result in emergence from anaesthesias that is influenced minimally by the duration of anaesthesia (context insensitive). Conflict of Interest:None declared |
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Andrew D Farmery Wadham College, Oxford
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Sir, I wish to comment of the interesting study by Nordmann and colleagues [1] in which isoflurane and desflurane anaesthesia were compared with respect to various indices of the speed of emergence, and in particular the 'exposure-time' sensitivity of these indices. Pharmacokinetic and mathematical models predict that emergence following desflurane would be quicker than that following isoflurane and this study usefully provides experimental confirmation of the hypotheses underlying these models. The authors state that younger children are less susceptible to delayed emergence following prolonged isoflurane exposure as compared to older/larger children. The evidence for this is not clear. Their figures 4 and 5 show a regression plot of 'time to extubation' vs. 'duration of anaesthetic', and for isoflurane the slope appears to be smaller for children <4yrs compared to >4yr. No statistical analysis for this comparison is presented, so it is not clear how the assertion is justified. Moreover, given that the data are non-parametric I am not sure that linear regression analysis is appropriate anyway. Whilst it is not my intention to criticise statistics, figure 4 particularly merits comment. It shows (to the naked eye) considerable scatter of points. Non-parametric data of this sort have characteristic outliers which defy analysis with linear regression (note the high outlier for isoflurane which will weight the linear regression slope). In addition, the 'range' of exposure-times is greater for isoflurane. Only the isoflurane group has data recorded for durations over 110 minutes. Desflurane data points do not have this breadth of span, and so with this degree of scatter bunched around a small x axis span, finding a regression coefficient around zero is more likely. This is not to say that I doubt the effect (I don’t), but this analysis does not seem to show it unequivocally. The authors offer an explanation as to why younger children are less susceptible to delayed emergence following prolonged exposure as compared to older/larger children. They suggest that this may be due to the larger tidal-volume:FRC ratio (i.e. ventilatory rate-constant) in younger children resulting in "more rapid exchange in alveolar gas, and therefore a faster elimination of the volatile agent". Mathematically this does not make sense. Certainly if we consider the non -steady state of an exponential washout (albeit achieved tidally) of a completely insoluble gas contained in the alveolar compartment, then reducing FRC for a given ventilation rate would indeed speed-up the washout. This might explain to some degree any differences between small and large children when considering speeds of wash-in or washout following short exposures (although this was not explicitly shown), but it cannot explain the 'exposure-time' sensitivity alone. The reason for this is that during emergence following prolonged exposure, the model moves away from that resembling exponential washout of helium from the alveolar compartment, to one more akin to steady-state (albeit drifting) alveolar elimination of anaesthetic agent delivered to the lung from the tissues via the blood. This more resembles the process of normal CO2 elimination than helium washout. Clearly increasing the VT:FRC ratio has no effect on CO2 elimination, which is dependent merely on the alveolar ventilation rate. Lastly, the authors ascribe the observed effects to the differences in the blood-gas partition coefficient between the two agents. Whilst this is certainly dominant factor (particularly in wash-in and wash-out after short exposure) it does not wholly explain exposure-time dependency (particularly since this characteristic is proposed to differ between small and larger children, yet the blood gas solubilities do not differ between these groups). There are two distinct processes underway during emergence: one is elimination of vapour from the alveolar compartment and the other is elution of agent from the tissues and subsequent transfer to the alveolar compartment. The dominance (and rate limiting effect) of one process over the other varies, and is key to overall elimination. Following prolonged anaesthesia, the elimination characteristics move away from the ‘non- steady-state helium washout’ type of kinetics to the ‘drifting-steady- state’ type, where alveolar elimination equals (or just exceeds) tissue elution rate. The effect of blood gas solubility is less dominant here. Mapleson’s 1973 model [2] of volatile agent kinetics is complex, but looked at very simply; there is a large reservoir of volatile agent; notably in fat. The capacity of this reservoir for an agent depends NOT on the agent’s blood gas solubility, but on its lipid solubility. The rate-constant for the washout (by the blood) of agent from the reservoir is a function of the volume of the reservoir, and the ratio of the ‘blood- gas’ to ‘tissue-gas solubility’. Desflurane’s blood gas solubility is threefold less than isoflurane, but its oil-gas solubility is five fold less than isoflurane. Hence the reservoir’s washout rate-constant is greater for desflurane than for isoflurane. So in summary, during emergence from desflurane anaesthesia, the lack of ‘exposure-time’ dependency is as much (or more) a function of its low potency (i.e. low lipid solubility) as its low blood-gas solubility. A D Farmery Wadham College, Oxford andrew.farmery@wadh.ox.ac.uk conflicts of interest: none References: 1. G. R. Nordmann, J. A. Read, S. M. Sale, P. A. Stoddart and A. R. Wolf. Emergence and recovery in children after desflurane and isoflurane anaesthesia: effect of anaesthetic duration. Br J Anaesth. 2006; 96(6):779-85 2. Mapleson WW. Circulation-time models of the uptake of inhaled anaesthetics and data for quantifying them. Br J Anaesth 1973;45(4):319-34 Conflict of Interest:None declared |
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