A Pharmacokinetic Simulation Programme For intravenous anaesthetics

Transcription

1 Version 3.1 A Pharmacokinetic Simulation Programme For intravenous anaesthetics Includes the interaction of opioids with propofol. Programmed in Delphi by F.Engbers, 1999 Manual: Nick Sutcliffe, March 2000 Glasgow, UK Aerdenhout, The Netherlands 07 March 2000 TIVAtrainer is a registered trademark of GuttaBV, Aerdenhout the Netherlands.

2 1 TIVAtrainer Manual INSTALLATION UNINSTALLATION AND COPY PROTECTION To install the programme put the disk in youre A drive. On your computer press Start then Run and type in A:\setup and press enter. Follow the instructions. Make sure the diskdrive is fully IBM compatible. Operating system requirements: Windows95 or Windows98. The standard version will not run from a network drive. The TIVAtrainer comes on a copy protected diskette. It is important that you keep this diskette in a save place. The diskette holds two unique keys (tokens) From every diskette you can install the programme on only two computers. During the installation one token is placed and fixed on your computer. Do not move the programme and do not copy it. You can uninstall the program by selecting the uninstall TIVAtrainer option under Start Programs TIVAtrainer. You will be asked to insert the original TIVAtrainer diskette. If you do so, the token will be put back on your diskette. If the diskette is not there, you will lose one installation option. Important: You must use the same diskette both for installation and uninstallation. You can move tokens back and forwards without having to uninstall the programme with the copy control utilities. Through the analyse button you can analyse the number of tokens left both on your hard disk and your installation diskette. Small updates or patches do not require new installation diskette. START A SIMULATION Open TIVAtrainer from the programme list. This opens to the main window with the logo visible. Click anywhere on the screen to clear the logo.

3 2 Along the top of the screen are the menu bar and icon/button bar. On this bar only 4 items are active from left to right new, folder icon, patient, help icon and exit icon Clicking new opens 2 windows the front window gives the patient default demographic details which can be changed and then must be accepted with OK before proceeding. The second window lists the drugs database from which the required drug can be selected. This can be done by double clicking a drug name or single clicking a drug name and then pressing OK. A graph is then opened in the main window with drug concentration on the left Y-axis, infusion rate on the right Y-axis and time in minutes along the X-axis Both Y-axes have up down arrows to alter the scale. Along the left side of the graph are 5 buttons: Manual, TCI, IVAssist, Options and Reset.

4 3 MANUAL MODE The default is manual for manual infusion and bolus regimen simulation. In Manual mode left clicking on the main graph at any time point allows a bolus and or infusion to be commenced at that time point. This action opens a window as above in which a bolus in units/kg or mls can be input and/or an infusion can be commenced in ml/hr or units/kg/time. The units are drug specific as is the concentration and can be modified from the options button see later. Clicking OK implements the set regimen: -

5 4 A graph is drawn of the selected regimen, the blue bar denotes the bolus dose the red line shows drug blood concentration and the green line the calculated effect site concentration. The infusion rate is shown by the white rectangle along the base of the graph. These are the default plots. However, these can be changed by use of the buttons on the right side of the main screen. Plots available are the above plus drug concentration in compartment 2 and 3 (default off) target level (TCI mode only default on), interaction and awake plots (see later). Boluses can be added and infusions changed at any time point in a similar manner simply by clicking at the desired time point and inputting the new regimen. RESET BUTTON Pressing the reset button deletes all data plotted on the graph after a confirmation prompt. TCI MODE Clicking on TCI converts the selected window to TCI (Target Controlled Infusion) mode. In this mode the user inputs a desired target blood concentration and TIVAtrainer calculates the infusion regimen required to achieve and maintain this blood concentration.

6 5 Left clicking at any time point on the drug window opens a box to input the desired target concentration. Typing this in the field and clicking OK implements the simulation from that time point. The target can be changed at any time by left clicking the graph at the desired time point and inputting a new target. As in manual mode the default plots are blood and effect site concentration and infusion rate, plus target concentration

7 6 IVASSIST MODE Whilst in manual mode the IVAssist button can be pressed, once this is done left-clicking on the graph area opens a different input box: The higher the accuracy the more step changes in infusion rate will be required (the accuracy is at the moment fixed at 95%) This allows a target effect site concentration to be input. TIVAtrainer can then calculated a bolus dose and stepped infusion regimen designed to achieve and maintain an approximate effect site concentration. This is similar to TCI, except it is the effect site, which is targeted, and there are a small number of changes in infusion rate which could in theory be achieved by manually adjusting an infusion pump. In the example shown below a target of 3 is selected to be maintained over 1 hour with 95% accuracy.

8 7 CONTROL OF AXES Y-axes The 2 Y-axes are easily controlled by the up and down arrow at the top of each axis, left clicking the up arrow increases the maximum value clicking the down arrow decreases it. X-axis The X-axis is controlled by 4 icons Left-clicking the magnifying glass zooms-out increasing the time window visible on screen. Clicking the + magnifying glass decreases the visible time window. The right arrow scrolls the active time window forwards in time the left arrow scrolls backwards. When scrolling backwards or reducing the time window visible the rubber icon becomes active this allows any data outside the maximum visible time window to be erased this can speed up some aspects of simulation, especially in long TCI simulations. You can specify the default simulation duration time in the settings menu. The next time you start TIVAtrainer it will use the selected time. TIME INDICATOR A small time window appears on the X-axis indicating the exact time of the current position of the cursor with respect to zero time. Clicking on the time (X-axis) at any point fixes the that point as zero with reference to the cursor position, moving the cursor from this point the time window indicates the elapsed time from the new zero to the current cursor position. Clicking on the zero reference point resets zero to time zero on the X-axis. When the cursor is at the time of an input the colour of this time window will be red. In the above example the time of the infusion starting was 12:55.

9 8 GRAPH TOOLS TIVAtrainer has a number of graph tools to help with presentation and demonstration of drug simulations. The icon/button bar at the top of the screen allows activation of these Left-clicking on patient allows the user to change the patient demographic data for the active drug window. The following graph tool buttons can be toggled on and off by left clicking them. The conc. button activates a concentration marker, which shows the drug concentration at the time point that the cursor is positioned. Blood effect site C2 and C3 concentrations are all displayed if active:

10 9 The rate and volume buttons switch on markers to show infusion rate and cumulative volume of drug infused respectively which move with the cursor position. When a bolus is simulated and the rate marker held over the bolus the volume of the bolus is displayed. Clicking the cost icon shows the cumulative cost of the drug at the point of the cursor. NB. The volume and cost marker cannot be displayed simultaneously. The cost data can be edited by accessing the cost data file from the edit drop down menu see later. Clicking the Decr. (Decrement) button displays a decrement marker. When the cursor is positioned on the graph below the current effect site concentration, this marker shows the time it would take for the effect site to fall to this value if the infusion was turned off. Clicking once on the graph fixes the marker so that it can only be moved in a vertical direction, a second click fixes it so it can only be moved in the horizontal direction. This is useful for demonstrating the effect of infusion duration on a drugs half-life (context sensitive halflife). A third click fixes the marker at that point while a forth click will free it again. Further over to the right are 3 icons three compartment graphic icon table icon and save table icon.

11 10 THREE COMPARTMENT GRAPHIC Clicking this button splits the screen in two with the main window on the left and the graphic window on the right. This contains a representation of the 3 compartments, it shows the blood concentrations in each compartment in graphical form. The middle compartment in C1 with a column up the middle to represent the effect site compartment with C2 shown to the left and C3 to the right, the size of the graphic is proportional to the actual compartment volumes. The connecting tubes are proportional to the intercompartimental clearances and the drug clearance. To demonstrate this function click on the icon and drag the left edge of the graphic window to the left to enlarge it to about half the screen. Moving the cursor over the main graph window give an indication on the graphic of the relative concentrations in each compartment at the time the cursor is positioned. With the scrollbar at the bottom of the screen the 3-compartment model is movable in the window allowing to show parts that are not visible.

12 11 TABLE FUNCTION Clicking on the table icon displays a table of the simulated data this can be exported to excel or a similar package by clicking the save table icon. If the table is visible, data can be copied to the windows clipboard by pressing Ctrl C or selecting copy table from the edit menu. If the table is not visible the chart itself will be copied as an enhanced metafile. This can be passed to other programs such as PowerPoint or word by clicking paste special and selecting windows metafile within that application. Only columns from which the heading is highlighted will be copied. You can highlight the heading by double clicking it or by selecting under file export table the columns you want. You can also specify the character that is used to separate the columns (delimiter). Default is the use of the Tab character. Please read the help file for additional information. OPENING MULTIPLE WINDOWS A number of drug windows can be opened at once. To open further windows click new and select another drug, by default the same patient details are retained, and the windows are tiled on screen. Any number of windows can be open simultaneously; only three to four windows can be usefully displayed. Drug windows can be minimised to the bottom of the screen, maximising them re-tiles them to the screen. All time axis changes are applied to all windows. Clicking any individual window makes this the active, changes in patient details, options or saving, applies to the active window. OPTIONS BUTTON Clicking the options button opens a window showing the default units and concentration for the selected drug window, and the pharmacokinetic data set used by the simulation. Any of these items can be edited, to simulate the effect of such changes. After you have edited the required changes you have to press the changed button to implement the changes. The system will recalculate changes in blood concentration based on the existing drug input in terms of bolus and infusion. If the simulation is saved as a template the changed pharmacokinetics are stored with the template. Important: If changed pharamcokinetics are used the dependency on patient parameters is lost. You can use two different notations for the pharmacokinetics: intercompartimental rate constants or Compartment volumes and clearances.

13 12 SAVING AND OPENING FILES Clicking on the save icon opens a comment window allowing a description of the file the authors name and a comment. Clicking OK then prompts for a file name and destination. Clicking the folders icon opens a window of saved files, the destination is defaulted the last saved location. Double clicking a file loads it into TIVAtrainer for long simulations this can take a few seconds. For identification the first column has the file name as saved in windows, the second column the drug used in the simulation file the third column is the description entered when the file was saved. For the selected file the comment entered during saving appears in the bottom left corner. A batch file can be created to load multiple simulation files. To do this click new in the batch file box within the save window enter a file name, then select a file to be included from the saved list, then click add in the batch file box. Any number of files can be added in this way. There is a small check box next to each file name if this is checked the file is loaded maximised if not it is loaded minimised. The batch file is then saved and appears in the saved window above. Double clicking a batch file loads all the included simulation files. Clicking the comment icon next to the folder icon displays and allows changes to be made the description and comments associated with the active drug window. INTERACTIONS TIVAtrainer has a drug interaction between opioids and hypnotics built into the program. This is based on the interaction described by Jaap Vuyk (1). In the program this can be implemented only when a propofol and an opioid window are open simultaneously. With a simulation active in both windows clicking on the interact button (just above the manual button on the opioid screen) displays an Cp 50 (Ec 50 ) and Cp 95 on the propofol graph. This is displayed as a grey band on the propofol graph the upper limit being the CP 95 the lower limit the Cp 50 for the given associated

14 13 opioid concentration i.e. the higher the opioid concentration the lower the Cp 50 and Cp 95 for propofol. Also displayed is the awakening concentration as a purple line this again is taken from the Vuyk paper. When the infusions are switched off as the effect site concentration plot crosses the awakening line the time from stopping the infusion and also the time from Cp50 to the awakening time is shown, as is the actual awakening concentration. It must be appreciated that the interaction is based a specific group of patients (young to middle age females having lower abdominal surgery without regional anaesthesia and without Nitrous oxide). It cannot be extrapolated to other situations and patients but does serve to give an indication of the effect of using different levels of opioid on hypnotic requirements. HELP FUNCTION The help button with a question mark on provides a limited help function. Click it then click over an icon or button to get some information about its function. Usually a link to the help file is available for additional help. Double clicking the question mark will open the help file. FAQ s Q: Can I use other kinetics for a drug?

15 14 A: Yes you can. In the option window you can specify the kinetics. You can setup a dosage and than half the clearance for example and see the resulting blood concentration. You cannot (yet) alter the database. If you save however the drug as a template the last used pharmacokinetics will be saved in the template. But you will always be able to use the original pharmacokinetics. Important: Changed pharmacokinetics saved in a template are not patient dependent. Q: Do I have to use the same patient characteristics for all simulations? A: No. Although you have to specify the patient characteristics for the first loaded drug, you can change the patient parameters for every simulation. Change of patient parameters will be indicated in the heading of the simulation window. If a simulation is stored as a template the patient characteristics are stored with it. If thereafter the template is loaded and the patient is different from the patient that is already introduced in the system, the user will be given the selection of using the patient data that was stored along with the patient or the patient data in the system. Q: I have got the disk but I cannot install it. A: Please check that you use Windows 95 or 98. Installation is not possible under Windows 3.1, Windows NT or Windows2000. The other possibility is that your disk is damaged or, very seldom, that your system cannot read the copy protected disk. Try the software on a different computer if possible. If you still encounter problems, send the disk back. The address is on the label. Q: Can I defragment a hard disk with installed TIVAtrainer A: Yes, no problem Q: Can I backup and restore a hard disk with installed TIVAtrainer. A: No you cannot. Uninstall TIVAtrainer first. Q: I have got a hard disk crash. A: For that reason you have two installation possibilities. Q: I do not have an interaction button/ the interaction button is not enabled/ nothing happens. The interaction only works from the opioids to propofol (in version 3). So only the opioids do have an interaction button and this button is only enabled in the presence of propofol. Only one propofol window, the first one, will take the interaction. Q: What happens if I select two opioids and press the interaction button in both simulations? A: The interaction is added according to the potency of the opioids. Q: Can I simulate effect compartment control? A: No, not in version 3 If you have any further question or suggestion how to improve the software or require functions that are not implemented yet please contact me via fengbers@wxs.nl Questions regarding the Tivatrainer will be anonymously published on the website from the Eurosiva: Check it regularly.

16 15 References 1. Vuyk J, Lim T, Engbers FHM, Burm AGL, Vletter AA, Bovill JG: The pharrnacodynamic interaction of propofol and alfentanil during lower abdominal surgery in female patients. Anesthesiology 1995; 83: Vuyk J, Mertens MJ, Olofsen E, et al. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology, Dec 1997, 87(6) p Coetzee J. F., Glen J. B; Wium C. A, Boshoff L; Pharmacokinetic Model Selection for Target Controlled Infusions of Propofol: Assessment of Three Parameter Sets. Anesthesiology, 1995,82:6 TIVAtrainer is a registered trademark of GuttaBV, Aerdenhout the Netherlands.