Mathematical method to build an empirical model for inhaled anesthetic agent wash-in
© Hendrickx et al; licensee BioMed Central Ltd. 2011
Received: 7 December 2010
Accepted: 24 June 2011
Published: 24 June 2011
The wide range of fresh gas flow - vaporizer setting (FGF - FD) combinations used by different anesthesiologists during the wash-in period of inhaled anesthetics indicates that the selection of FGF and FD is based on habit and personal experience. An empirical model could rationalize FGF - FD selection during wash-in.
During model derivation, 50 ASA PS I-II patients received desflurane in O2 with an ADU® anesthesia machine with a random combination of a fixed FGF - FD setting. The resulting course of the end-expired desflurane concentration (FA) was modeled with Excel Solver, with patient age, height, and weight as covariates; NONMEM was used to check for parsimony. The resulting equation was solved for FD, and prospectively tested by having the formula calculate FD to be used by the anesthesiologist after randomly selecting a FGF, a target FA (FAt), and a specified time interval (1 - 5 min) after turning on the vaporizer after which FAt had to be reached. The following targets were tested: desflurane FAt 3.5% after 3.5 min (n = 40), 5% after 5 min (n = 37), and 6% after 4.5 min (n = 37).
Solving the equation derived during model development for FD yields FD=-(e(-FGF*-0.23+FGF*0.24)*(e(FGF*-0.23)*FAt*Ht*0.1-e(FGF*-0.23)*FGF*2.55+40.46-e(FGF*-0.23)*40.46+e(FGF*-0.23+Time/-4.08)*40.46-e(Time/-4.08)*40.46))/((-1+e(FGF*0.24))*(-1+e(Time/-4.08))*39.29). Only height (Ht) could be withheld as a significant covariate. Median performance error and median absolute performance error were -2.9 and 7.0% in the 3.5% after 3.5 min group, -3.4 and 11.4% in the 5% after 5 min group, and -16.2 and 16.2% in the 6% after 4.5 min groups, respectively.
An empirical model can be used to predict the FGF - FD combinations that attain a target end-expired anesthetic agent concentration with clinically acceptable accuracy within the first 5 min of the start of administration. The sequences are easily calculated in an Excel file and simple to use (one fixed FGF - FD setting), and will minimize agent consumption and reduce pollution by allowing to determine the lowest possible FGF that can be used. Different anesthesia machines will likely have different equations for different agents.
What fresh gas flow - vaporizer setting (FGF - FD) combination should be used for a particular patient when starting the administration of potent inhaled anesthetics to reach a target end-expired concentration (FA) after a predetermined time interval without excessively wasting potent inhaled anesthetic? The wide range of FGF - FD combinations used by different anesthesiologists during the wash-in period of potent inhaled anesthetics indicates that the selection of FGF and FD is based on habit and personal experience. Some anesthesiologists use a high FGF (to shorten the wash-in time constant of the anesthesia circle breathing system, and to avoid rebreathing that results in dilution of FD), while others prefer to use a lower FGF in combination with a higher FD (to compensate for the longer wash-in time constant, and to reduce agent consumption). While all anesthesiologists swiftly attain the target FA (FAt) because FGF and FD can be adjusted according to the measured FA, it is unlikely that the particular FGF - FD combination used was that with the least number of FD and FGF adjustments and minimum waste. The use of high FGF, even for a seemingly brief period (5 min), may increase agent consumption above that of an ensuing one hour maintenance phase with a 1 L. min-1 FGF , and may forfeit the savings of an automated closed-circuit anesthesia machine .
Instead of relying on personal preference, we hypothesize that very specific FGF - FD combinations can be used in the individual patient to attain a FAt within a specified time interval by using an empirical model of the kinetics of inhaled anesthetics during wash-in. Simple, easy to remember FGF - FD combinations construed from these models could reduce agent consumption while not distracting the anesthesiologist from other tasks during the induction period of anesthesia .
While kinetics of inhaled anesthetics in the anesthesia circle system have already been modeled using mass balances [4–6], few of these models have been tested prospectively [3, 7]. We developed an empirical model for desflurane administered in O2 with an ADU - AS/5® anesthesia machine (Anesthesia Delivery Unit, General Electric, Helsinki, Finland) during the first 5 min of the anesthetic, and prospectively tested whether it allows the anesthesiologist to select a FGF - FD combination to attain a FAt of the inhaled anesthetic within a specified time interval (1 - 5 min) after turning on the vaporizer.
Part I. Model development
After obtaining IRB approval (OLV Hospital, Aalst, Belgium) and written informed consent, 50 ASA physical status I or II patients presenting for plastic, urologic, or gynecologic surgery were enrolled. All patients received oral alprazolam (0.5 or 1.0 mg) 1 h before the scheduled start of surgery. After preoxygenation (8 L. min-1 O2 FGF for 3 min), propofol (3 mg. kg-1), rocuronium (0.7 mg. kg-1), and sufentanil (0.1 μg. kg-1) were administered intravenously. After tracheal intubation, ventilation was mechanically controlled by an ADU anesthesia machine. Tidal volume and respiratory rate were set fixed at 500 mL and 10 breaths. min-1, respectively.
In a particular patient, one (fixed) O2 FGF and desflurane FD combination was used, with the FGF ranging from 0.5 tot 5 L. min-1 and FD from 6 to 18%; this FGF - FD combination was chosen randomly (random function in excel). Preliminary trials indicated what combinations were likely to lead to a desflurane FA less than 1% after 2 min or less than 2% after 5 min, and these were not considered.
Inspired and expired gases were analyzed by a multigas analyzer (Datex-Ohmeda Compact Airway Module M-CAiOV®, Datex-Ohmeda, Helsinki, Finland) and downloaded into a spreadsheet every 10 seconds. Gases were sampled at the distal end of the endotracheal tube using a piece of sampling tubing placed through an Arndt Multi-Port Airway Adapter® (Cook Medical Inc., Bloomington, IN). Gases sampled by the gas analyzer were redirected to the anesthesia circuit via the expiratory limb. The study was terminated after 5 minutes, or earlier when the end-expired desflurane concentration had reached 8%. All values above 8% were eliminated from further analysis. The 5 min period was somewhat arbitrarily defined as the wash-in period because it encompasses (1) anesthesia circuit wash-in; (2) FRC wash-in; (3) early uptake by the VRG; (4) and the waning effects of propofol after about 5 min.
A model was build to relate FA to FGF, FD, time, and the following patient covariates: age, height, and weight. A constant ventilation allowed us to at least standardize circuit and FRC wash-in; after 5 min, ventilation can easily be adjusted to the desired end-expired CO2 concentration. All values before 1 min were deleted because zero values are hard to work with mathematically, and because the model was only supposed to model the FGF - FD - time relationship between 1 and 5 min. Initial model building and parameter exploration were done in Excel using Solver® (Microsoft, Seattle, WA). The initial choice of mathematical functions was guided by three assumptions. First, because FA rises exponentially, a one exponential function was used to describe the rise of FA. Second, the effect of a higher FD was modeled as curvilinear (assuming, for example, that doubling FD would lead to a doubling of FA). Third, the effect of FGF was modeled with a single exponential (increasing as FGF is lowered). By trial and error, these and additional functions were added, deleted, modified, etc. to minimize the sum of least squares (difference between measured and predicted FA) using Solver (Excel). Residuals were plotted against height, weight, and age to search for covariate effects by visual inspection and by linear regression. Finally, the model was tested for parsimony using NONMEM's Minimum Objective Function (ICON Development Solutions, Dublin, Ireland).
Part II. Prospective testing
The model equation derived in part I was solved for FD using Mathematica (Mathematica for Windows, Version 4.0, Wolfram Research Inc, Champaign, IL). The resulting equation predicts the FGF - FD combinations the anesthesiologist can use to attain a FAt within the same time interval used during model development (i.e., between 1 and 5 min) using a single FD and FGF setting, and takes into account the covariate effects derived during model building (see results section for actual equation).
Management of the patients during prospective testing only differed in the manner in which FGF and FD were selected. Patients received desflurane in O2 with the goal to reach a FAt of 3.5% after 3.5 min (n = 40), 5% after 5 min (n = 37), or 6% after 4.5 min (n = 37). The number of patients was chosen based on prior experience. After entering the time and FAt as well as significant patient covariates in the equation, the equation describes all possible FGF - FD combinations that reach the FAt at the desired time for a patient with the particular characteristics entered into the equation. The fixed FGF that was going to be used in the individual patient was randomly selected (using Excel's random function) and entered in the equation, yielding the FD to be used. Because the resolution of the desflurane vaporizer is 0.5%, the nearest value was chosen. FGF values requiring an FD above the vaporizer limit (18%) obviously could not be tested.
To allow us to compare model performance between the three subgroups (3.5% after 3.5 min, 5% after 5 min, or 6% after 4.5 min), the performance error (PE) for each patient was calculated as 100*((FA measured - FA predicted)/FA predicted), and the absolute performance error (APE) as the absolute value of PE. Next, for each subgroup, the following were examined: (1) bias and accuracy, using the median performance error (MDPE, median of all PE) and median absolute performance error (MDAPE, median of all APE) ; (2) the relationship between FGF and PE (and APE) using linear regression (linear correlation) and a third order polynomial (non-linear effects) to help assess whether the model systematically over- or underestimated the end-expired desflurane concentration with increasing FGF.
Part I. Model derivation
Patient demographics, presented as mean (standard deviation)
Model derivation group
3.5% after 3.5 min group
5% after 5 min group
6% after 4.5 min group
Part II. Prospective testing
An empirical equation can be derived that predicts FGF - FD combinations that attain a FAt of an inhaled anesthetic after a predefined time lag. With modern computing power such an equation can easily be entered into an Excel file to calculate the required FD for any chosen FGF. While our current model will need to be refined and tested for different patient populations, agents, carrier gases, and anesthesia machines, our results prove the concept.
The concept of using an equation to predict the required FD for any chosen FGF to help the anesthesiologist attain and maintain a FAt is not new. Three decades ago, Lowe described a "general anesthetic equation" that describes the FGF - FD relationship in a circle breathing system . That equation was derived by considering mass balances in the circle system and by making certain assumptions regarding the uptake pattern of the agent (the square root of time model) . The model was mainly developed to facilitate the use of closed circuit anesthesia, and has never been tested prospectively across the entire FGF spectrum. Our current empirical model only describes the first 5 min of inhaled agent administration, the wash-in phase, and is to be combined (in the future) with a model that predicts the FGF - FD relationship during the maintenance phase.
The MDPE (-2.9, -3.4, and -16.2%) as well as the MAPDE (7.0, 11.4, and 16.2%) are within the limits deemed acceptable for target controlled infusion systems for intravenous anesthetic agents (MDPE <10-20% and MDAPE 20 - 40%) . Still, there is some degree of misspecification of the model that could not be accounted for: there are some outliers of 30%, and the error seems larger in the lower FGF range. The latter could be explained by the fact that uptake differs almost 170% among patients [10, 11]. This variability in uptake may have a more pronounced effect on FA with lower FGF because increased rebreathing causes the effect of the (unpredictable) amount of uptake on the composition of the inspired mixture to become more pronounced. During modeling, attempts are made to improve the degree of misspecification by taking the effect of covariates into account. However, only height significantly decreased the minimum objective function. Weight (within the range encountered in the study population) has previously been shown not to correlate with agent uptake [10–13]. Therefore, it is no surprise that weight did not improve the minimum objective function during model development, and that there was no significant effect of weight as a covariate. Nevertheless, future modeling in a still larger patient group might reveal for example that lean body weight might be a useful covariate. Age did not improve NONMEMs minimum objective function during model development either, but visual inspection of the FA versus age plot during prospective testing suggests FA to be higher with older age (r2 ranged from 0.04 - 0.18). Age might therefore still turn out to be a useful covariate in a new model based on a larger number of patients. Other factors may be important - it may be that model misspecification increases with altered physiology and pathophysiology, e.g. when older, sicker patients are included (patients in this study were relatively healthy - ASA 1-2), when cardiac output is altered, or when synergistic effects are likely to come into play (e.g. with premedication).
Other limitations exist. The wash-in model may not be applicable when spontaneous ventilation is allowed immediately following intravenous induction of anesthesia, because the irregular and inconsistent breathing at that time does not allow the acquisition of reliable end-expired concentrations. This also is an issue for modern anesthesia machines that use automated closed-loop end-tidal feedback administration of inhaled agents. Also, the model is limited to a maximum end-expired concentration of 8% - higher concentrations might be needed in some patients, but this comes at a risk of irritating the airway.
An empirical model is described that allows the derivation of a formula for each type of anesthesia machine that predicts the FGF - FD combinations in a circle breathing system that attain a target end-expired agent concentration in a particular patient within a specified time interval (1 - 5 min) after turning on the vaporizer. The sequences are easily calculated in an Excel file and simple to use (one fixed FGF - FD setting), and have the potential to minimize agent consumption and reduce pollution by allowing to determine the lowest possible FGF that can be used.
Appendix: Derivation of Figure 6
According to the model, FA = (1/(Ht*0.1))*(2.55*FGF+1348*(1-e(-FGF*-0.23)+2.49*(1-e(-FGF*0.24))*0.39*FD)*(0.03*(1-e(Time/-4.08)))) with Ht = height (cm), Time = time after turning on the vaporizer (min), and with FA, FD and FGF expressed in %, %, and L. min-1, respectively.
Similar graphs can be developed for different time intervals (between 1 and 5 min). The multicolored surface in Figure 7 describes the desflurane FA after using a range of FGF - FD combinations for 5 min; the intersection between this surface and the target 4.5% surface (horizontal light blue surface) thus describes the virtually infinite number of FGF - FD combinations that result in an FA of 4.5% after 5 min in a 176 cm tall patient (Figure 8). Figure 6 is a composite of these graphs for the time intervals of 1, 2, 3, 4, and 5 min with a FAt of 4.5%.
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