Control device for controlling the administration of propofol to a patient

Abstract

The invention relates to a control device for controlling the administration of propofol to a patient according to the preamble of claim 1 and to a method for controlling the administration of propofol to a patient according to the preamble of claim 4. With a method of this kind a bispectral index (BIS) target value is set which shall be, at least approximately, reached within a patient. A controller then computes a recommended infusion rate of propofol based on the target BIS value and further based on a measured propofol level of the patient for administering propofol to the patient. The controller herein comprises a model unit for computing the recommended infusion rate such that, using the model unit for determining the propofol sensitivity of a patient by means of a mathematical model taking into account the bispectral index (BIS) value and optionally the measured propofol level as input variables, the recommended infusion rate for administering propofol to the patient to achieve the BIS target value may be determined.

Claims

1. A control device for controlling the administration of propofol to a patient comprising a human machine interface, an infusion pump which comprises a controller for computing a recommended infusion rate for administering propofol to the patient, a depth-of-anesthesia monitor, a target setting unit for setting a BIS target, and a model unit for determining the propofol sensitivity of a patient by means of a mathematical model taking into account the bispectral index (BIS), wherein the mathematical model is based on a PK/PD model which comprises a 3+1 PK/PD model, a remote compartment X and a compartment S; wherein the compartment S represents the bisprectral index (BIS) and is represented by the following equation: $S=\frac{s_{p}X}{{\alpha }_M+X}-k_{b0}S+\mathrm{OF}$ wherein s.sub.P represents the propofol sensitivity of the patient; α.sub.M represents the saturation parameters of the velocity of effect of an anesthetic; k.sub.b0 represents the decay rate of the BIS index; OF represents the offset that can remain when no more anesthetic is present in the patient body; X represents a remote compartment; and S represents a BIS sensor and the remote compartment X models the delay between the propofol concentration in the effect site compartment and its actual impact on the bispectral index (BIS).

2. The control device according to claim 1, wherein the infusion pump further comprises at least one actuator.

3. The control device according to claim 1, wherein said control device is based on a closed-loop system, wherein an infusion rate of propofol is sent automatically by the controller to the infusion pump for administering propofol to the patient.

4. The control device according to claim 1, wherein the 3+1 PK/PD model is based on a central compartment A comprising a blood concentration C.sub.p of propofol, a rapid equilibrating compartment C.sub.RD, a slow equilibrating compartment C.sub.SD, an effect compartment E comprising an effect compartment concentration C.sub.e of propofol.

5. The control device according to claim 1 further comprising a drug sensor, and the mathematical model taking into account the measured propofol level.

6. The control device according to claim 1 wherein a propofol level measurement is performed automatically and periodically at predefined measurement times for providing a feedback to the controller.

7. The control device according to claim 1, further comprising a drug sensor.

8. The control device according to claim 7, wherein the compartments of the PK/PD model are re-estimated in real-time.

9. The control device according to claim 7, wherein the controller is a model-based controller.

10. The control device according to claim 7, wherein the controller allows the plugging and unplugging of the drug sensor.

11. The control device according to claim 7, wherein the compartments of the PK/PD model are re-estimated in real-time using a Luenberger observer.

12. The control device according to claim 1, wherein {circumflex over (k)}.sub.1e and {circumflex over (k)}.sub.e0 are model parameters that are defined below and readjusted in order to have, at the time of loss of consciousness, the effect compartment concentration C.sub.e equal to the value C.sub.e50 as set out in a first equation:
C.sub.e(t.sub.LOC,{circumflex over (k)}.sub.e0,{circumflex over (k)}.sub.1e)≡C.sub.e50 wherein C.sub.e represents the effect compartment concentration; t.sub.LOC represents the time point of loss of consciousness; k.sub.e0 defines the proportional change in each unit of time of the concentration gradient between the plasma and effect-site, k.sub.1e describes an elimination constant for redistribution of propofol from the effect compartment E to the central compartment A; and wherein C.sub.e50 represents the effect compartment concentration at the EC.sub.50 point according to a second equation: $C_{e50}=\frac{{\left(E_0-\mathrm{Effect}\right)}^{\frac{1}{y}}.Math.{\mathrm{EC}}_{50}}{{\left(E_{\max }-\left(E_0-\mathrm{Effect}\right)\right)}^{\frac{1}{y}}}$ wherein Effect represents the concentration-effect relationship between EC.sub.50 and the BIS index, wherein the second equation is deduced from a third equation: $\mathrm{Effect}=E_0-\frac{E_{\max }.Math.{C_{e50}}^y}{{{\mathrm{EC}}_{50}}^y+{C_{e50}}^y}$ wherein in the second equation and the third equation: E.sub.0 represents the initial value of the BIS effect at time point zero; E.sub.max represents the maximum value of the BIS effect; y represents the Hill coefficient; EC.sub.50 defines how much drug needs to be administered to obtain an effect in 50% of the patient population.

13. The control device according to claim 12, wherein said control device takes into account interactions of propofol with other drugs comprising analgesics, said analgesics including Alfentanil and Remifentanil.

14. The control device according to claim 13, wherein the PK/PD model is recalibrated, after at least one analgesic has been administered.

15. The control device according to claim 1, wherein the delay which the remote compartment X models between the propofol concentration in the effect site compartment and its actual impact on the bisprectral index (BIS), comprises physiological delay, and computational delay induced by signal processing in the bispectral index (BIS).

16. The control device according to claim 15 wherein remote compartment X is represented by the following equation:
X=s.sub.2C.sub.e−S.sub.1X wherein s.sub.1 and s.sub.2 represent constant transfer rate parameters between the remote compartment X and the effect compartment E; C.sub.e represents the effect compartment concentration; and X represents a remote compartment.

17. A method for controlling the administration of propofol to a patient, comprising the steps of: setting a target BIS value on a BIS sensor, and setting a controller to compute a recommended infusion rate for administering propofol to the patient based on the target BIS value, estimating a propofol sensitivity of the patient with the use of a mathematical model taking into account the bispectral index (BIS) wherein the mathematic model is based on a PK/PD model comprising a 3+1 PK/PD model, a compartment S representing a BIS sensor and is represented by the following equation: $S=\frac{s_{p}X}{{\alpha }_M+X}-k_{b0}S+\mathrm{OF}$ wherein s.sub.p represents the propofol sensitivity of the patient; α.sub.M represents the saturation parameters of the velocity of effect of an anesthetic; k.sub.b0 represents the decay rate of the BIS index; OF represents the offset that can remain when no more anesthetic is present in the patient body; X represents a remote compartment; and S represents a BIS sensor, and a remote compartment X modeling the delay between the propofol concentration in the effect site compartment and the actual impact on the BIS sensor, and tuning parameters of the mathematical model according to the depth of anesthesia and/or the level of the anesthetic in the body of said patient.

18. The method according to claim 17 wherein the controller computes a recommended infusion rate for administering propofol to the patient based on the measured propofol level of the patient.

19. The method according to claim 17, wherein the 3+1 PK/PD model is based on a central compartment A comprising a blood concentration C.sub.p of propofol, a rapid equilibrating compartment C.sub.RD, a slow equilibrating compartment C.sub.SD, an effect compartment E comprising an effect compartment concentration C.sub.e of propofol.

Description

(1) The idea underlying the invention shall subsequently be described in more detail with regard to the embodiments shown in the figures. Herein:

(2) FIG. 1 shows the relationship between the propofol effective concentration 50 (EC.sub.50) and the bispectral index (BIS);

(3) FIG. 2 shows a schematic diagram of the 3+1 PK/PD model as known in the prior art;

(4) FIG. 3 shows a schematic diagram of the extended 3+1 PK/PD model of the instant invention;

(5) FIG. 4 shows a schematic diagram of the control device; and

(6) FIG. 5 shows a concentration-time diagram, displaying different aggressiveness of the controller.

(7) FIG. 1 shows the relationship between the propofol effective concentration 50 (EC.sub.50) and the bispectral index (BIS). FIG. 1 has been disclosed in the publication from T. A. Lim “Relationship between bispectral index and effect-site EC.sub.50 for propofol” Br J Anaesth, 2006, 267-268, where corroborating results on different patient populations were reviewed and summarized. This information provides a way to relate the effect-site concentration and the bispectral index (BIS) at defined points, such as at loss of consciousness (LOC) or at the point of anesthesia.

(8) The concentration-effect relationship between EC.sub.50 and the BIS illustrated in FIG. 1 is derived by the equation according to Hill as follows:

(9) $\mathrm{Effect}=E_0-\frac{E_{\max }.Math.{C_{e50}}^y}{{{\mathrm{EC}}_{50}}^y+{C_{e50}}^y}$

(10) wherein EC.sub.50=4.14 μg/ml for propofol, E.sub.max=E.sub.0=100 and y=2.

(11) FIG. 2 shows a schematic diagram of the 3+1 PK/PD model as known in the prior art. Said 3+1 PK/PD model comprises a central compartment A comprising a blood concentration C.sub.p of propofol, a rapid equilibrating compartment C.sub.RD, a slow equilibrating compartment C.sub.SD, an effect compartment E comprising an effect compartment concentration C.sub.e of propofol.

(12) wherein Q represents an administered drug, k.sub.e0 defines the proportional change in each unit of time of the concentration gradient between the plasma and effect-site, k.sub.1e describes an elimination constant for redistribution of propofol from the effect compartment E to the central compartment A, k.sub.12 is an elimination constant describing the distribution of the volume V1 in direction of volume V2, k.sub.21 is an elimination constant describing the distribution of the volume V2 in direction of volume V1, k.sub.13 is an elimination constant describing the distribution of the volume V1 in direction of volume V3, k.sub.31 is an elimination constant describing the distribution of the volume V3 in direction of volume V1, k.sub.10 represents the elimination constant of a n applied drug, such as propofol from the body.

(13) FIG. 2 visualizes the so called Schnider model, which can be described as follows: After intravenous injection, a drug Q is rapidly distributed in the circulation (called the central compartment A) and quickly reaches well perfused tissues. Then, a tissue-specific redistribution in various other compartments such as muscle or fat tissue and vice versa from the central compartment A occurs. At the same time the body eliminates the applied substance from the central compartment with a certain elimination rate. For the pharmacokinetic characterization of lipophilic anesthetics, a 3-compartment model has been established that comprises a central compartment A (heart, lung, kidney, brain), a rapid equilibrating compartment C.sub.RD (muscles, inner organs), and a slow equilibrating compartment C.sub.SD (fat, bone, the so-called “deep” compartment). The concentration-time curve of a drug is characterized by the distribution volume of a specific compartment and the clearance (which is the plasma volume, from which the drug is eliminated per time unit): V1 is used as the volume of the central compartment A, V2 as the volume of the well-perfused tissue C.sub.RD and V3 as the volume of the rather worse perfused compartment C.sub.SD. The clearance of a substance from the various compartments can be described by elimination constants and included by definition, a description of the distribution direction: The elimination constant k.sub.12 for example, describes the distribution of the volume V1 in direction V2, k.sub.21 describes the distribution in the opposite direction. An applied substance is eliminated by this model with the constant k.sub.10 from the body. After reaching an equilibrium (“Steady state”) between the individual compartments, the elimination rate determines the amount of substance that must be supplied to maintain equilibrium. An intravenously administered anesthetic is first distributed within the central compartment A. From there, the distribution will take place into the effect compartment E and into the peripheral compartments. The substance is eliminated by the constant k.sub.10 from the central compartment A.

(14) To assess the clinical effect (the so-called pharmacodynamics) of a drug at the target site, dose-response curves are used. These usually sigmoidal extending curves describe the association between drug concentration and the particular clinical effect. Knowing these dose-response relationship, a putative drug concentration at the site of action, the effect compartment E, can be calculated. The delay between the maximum plasma concentration and the maximum clinical effect is called hysteresis.

(15) FIG. 3 shows a schematic diagram of the extended 3+1 PK/PD model of the instant invention, which additionally comprises a remote compartment X and a BIS sensor S,

(16) wherein s1 and s2 represent constant transfer rate parameters between the remote compartment X and the effect compartment E, S.sub.P represents a transfer rate coefficient between the remote compartment X and the depth-of-anesthesia monitor S, and k.sub.b0 represents the decay rate of the BIS index.

(17) Clinically, S.sub.P can be seen as the propofol sensitivity. The higher the value of S.sub.P is, the faster is the propofol effect achieved. High values of S.sub.P further lead to a short delay of the system and a high responsiveness of the system.

(18) The remote compartment X describes the delay between the propofol concentration in the effect-site compartment and its actual impact on the BIS value.

(19) The compartment S represents a patient-dependent BIS sensor, i.e. the actual BIS value displayed on the monitor.

(20) FIG. 4 shows a schematic diagram of the control device for controlling the administration of propofol to a patient comprising a human machine interface (1), an infusion pump (2) which comprises a controller (3) for computing a infusion rate for administering propofol to the patient, a depth-of-anesthesia monitor (6), such as a bispectral index (BIS) monitor, and optionally a drug sensor (7), which further comprises, in accordance with the invention, a target setting unit (5) for setting a BIS target value and a model unit (4) for determining the propofol sensitivity of a patient by means of a mathematical model taking into account the bispectral index (BIS) and optionally the measured propofol level. The control device may further comprise at least one actuator. Actuators in the sense of the present invention are any mechanical parts of the infusion pump, including for example a motor or other mechanical parts between the model-driven controller and the injection syringe.

(21) Typically, when using the control device according to the invention, the operator first plugs on the depth-of-anesthesia monitor (6), such as a BIS monitor. The operator is typically an anesthetist or an anesthesia nurse. Thereafter, a model for target controlled infusion (TCI) for propofol is chosen and set in the control device.

(22) TCI models for propofol are known in the art. The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting. With effect-site targeting the goal is to achieve a user-defined target effect-site concentration as rapidly as possible, by manipulating the plasma concentration around the target. Currently systems are pre-programmed with the Marsh (B. Marsh et al., “Pharmacokinetic model driven infusion of propofol in children” Br J Anaesth, 1991; 67, pages 41-48) and Schnider (Thomas W. Schnider et al., “The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers”, Anesthesiology, 1998, 88(5) pages 1170-82) pharmacokinetic models for propofol. The former is an adapted version of the Gepts model, in which the rate constants are fixed, whereas compartment volumes and clearances are weighed proportional. The Schnider model was developed during combined pharmacokinetic-pharmacodynamic modelling studies. It has fixed values for certain parameters, such as k.sub.13, and k.sub.31, adjusts others, k.sub.12, and k.sub.21 for age, and adjusts k.sub.10 according to total weight, lean body mass (LBM), and height. In plasma targeting mode, the Schnider model starts with smaller initial doses on starting the system or on increasing the target concentration in comparison with the Marsh model. The Schnider model should thus always be used in effect-site targeting mode, in which larger initial doses are administered, albeit still smaller than for the Marsh model.

(23) Having chosen the appropriate TCI model, the operator (8) has then to enter patient parameters, such as age, gender, total weight, lean body mass (LBM) and height, for example. After the synchronization of the model/BIS in order to tune the OFFSET parameter of the model has occurred, the BIS target value (5) has to be set by the operator (8). It can further be chosen whether the control device works in ramp mode or not, wherein ramp mode has been demonstrated as best practice to increase the patient's sensitivity to propofol. Ramp mode means that a desired BIS target value is not reached in a direct, linear manner, but in a stepwise manner. In contrast, if ramp mode is not chosen, a time for achievement a BIS target value is to be set, representing the aggressiveness of the controller. In the next step, the protocol is started. At the point of loss of consciousness (LOC), the operator typically will click on the LOC button on the system (infusion pump or machine). This will give a feedback to the protocol that the EC.sub.50 has been reached and will recalibrate the model according to the patient parameters and the actual BIS value. To further improve precision, the physician optionally informs the system at the EC.sub.95 value. Several techniques exist to determine this value easily during the surgery, e.g. just before starting surgery.

(24) FIG. 5 shows a concentration-time diagram, displaying different aggressiveness of the controller. As described for FIG. 4, the operator sets a BIS target value to the infusion pump and the controller uses the PK/PD model to compute the correct infusion rate to administer propofol to the patient to achieve the BIS target value. The controller of the invention (optionally in combination with PID controller with Smith predictor) is capable of avoiding overdosing of propofol when using a system with high delay. The controller can predict different scenarios in the future using trajectory generation and tracking to achieve the desired BIS target value. This technique further enables the operator to choose the time of target achievement, i.e. to choose the “aggressiveness” of the controller. FIG. 5 shows exemplary different “aggressiveness” trajectories of the controller. Short-dashed line, semi-dashed line and plain line represents high, medium and low aggressiveness, respectively.

(25) Accordingly, the invention further provides a method of using of the control device according to invention, comprising the steps of: a) plugging the depth-of-anesthesia monitor (6), b) choosing a TCI model and entering patient parameters, c) waiting for TCI model/BIS synchronization, d) setting the BIS index target (5), e) selecting ramp mode or not, f) starting the protocol, g) at loss of consciousness point, clicking on the LOC button on the infusion device, such as the infusion pump or the infusion machine, h) optionally, informing the control device at the EC.sub.95; and i) further optionally choosing the time of target achievement (aggressiveness of the controller).

(26) The idea of the invention is not limited to the embodiments described above.

(27) In particular, the system described above in principal may also be set up as a closed-loop system which does not require interaction by an operator. For this, an infusion rate may automatically be sent by the controller to the infusion pump for administration of propofol to the patient, and a propofol level measurement may be taken automatically, for example in a periodic fashion at predefined measurement times for providing a feedback to the control device.

LIST OF REFERENCE NUMERALS

(28) 1 Human machine interface 2 Infusion pump 3 Controller 4 Model unit 5 BIS Target value 6 BIS Monitor 7 Drug Sensor 8 Operator 9 Actuator 10 Patient A Central compartment E Effect compartment Q Administered drug infusion rate