Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
  • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
  • A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
  • A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
  • A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
  • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
  • G16H20/17—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients delivered via infusion or injection
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
  • G16H50/50—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders

Definitions

• the invention relates to a device for the time-controlled dosing of the anesthetic propofol by means of a method for determining a corresponding dosing profile and corresponding control of an infusion pump as a dosing device.
• anesthesia course should be similar to a rectangular pro 1, i.
• the anesthesia should be initiated quickly at a precisely defined time, then maintained at a constant level over a certain period of time, and discharged again just as quickly after completing the procedure.
• An anesthetic must be administered at an appropriate rate of infusion over time.
• electronically controlled infusion pumps are used in medicine, via which the infusion rate can be programmed.
• the temporal profile of action of the anesthetic which determines the course of anesthesia, in addition to the infusion rate but also by a number of patient-individual anatomical, physiological, biochemical and genetic factors is affected.
• the anesthetic reaches the systemic circulation of the patient, the substance is distributed in the organism.
• the anesthetic is transported via the blood flow into the various organs, where it finally spreads into the cells.
• This organ distribution kinetics is e.g. individual blood flow rates of individual organs, which in some subpopulations (e.g., children, elderly, sick, pregnant women) differ markedly from those of typical, healthy adults.
• the clearance ie the rate of metabolism in the excretory organ (usually the liver, sometimes also other organs such as the intestine or kidney) determines the kinetics of elimination, which is of central importance for the maintenance and discharge of anesthesia.
• This clearance is also highly dependent on individual factors of the particular patient, e.g. Age, sex, level of expression of the metabolizing enzymes and blood flow rate of the eliminating organ.
• the temporal concentration course of the narcosis agent at its site of action, the brain is of particular interest because it determines the course of anesthesia.
• TCI Target Controlled Infusion
• a commercial infusional pumpi control system exists, marketed as Diprifusor TM by AstraZeneca - product information "Diprifusor TM: Target Controlled Infusion (TCI) in anesthetic practice", AstraZeneca Anesthesia, New Edition (1998).
• TCI Target Controlled Infusion
• Another infusion system specifically for pediatric use is under development (Paedfusor, Munoz HR, Cortinez LI, Ibacache ME, Altmann C.
• the central compartment in this three-compartment model represents the blood pool
• the one peripheral compartment is the so-called "effect compartment", which describes the time course of the concentration of the anesthetic at its site of action
• the third compartment represents organs with low blood perfusion
• the Patient-individual input variables of these systems are the age, body weight, and a target concentration in the patient's blood
• the infusion rate to be applied is determined on the basis of an open three-compartment experimental data.
• the body weight normalized blood flow rate in a two-year-old child is twice as high as that of a five-year-old child (Wintermark M, Lepori D, Cotting J, Roulet E, van MG, Meuli R et al., Brain perfusion in children: evolution with age) by quantitative perfusion computed tomography, Pediatrics 2004; 113 (6): 1642-52), a fact that can not be described by an age-independent mass transfer rate in the effect compartment (k e o).
• the age-related differences in the composition of the body in terms of its relative proportions of water, fat, and protein significantly affect the volume of distribution and thus the kinetics of propofol.
• the pharmacokinetics of propofol in obese patients are not solely dependent on body weight but rather on fat content.
• the volume of the central compartment is similar in obese and normal weight people, which can be explained by a comparatively small variability in the volume of well-perfused tissue between such individuals.
• the peripheral compartments, in particular that which represents the poorly perfused tissues, on the other hand, are distinctly different, which leads to a larger distribution volume in obese individuals.
• the times until induction of general anesthesia are similar, but the elimination is faster in obese patients (Servin F, Farinotti R, Haberer J, Desmonts J.
• Newborns therefore wake up more quickly from general anesthesia after the end of the propofol infusion, but they only recover relatively slowly from the subsequent symptoms, which is attributable to reduced systemic clearance (Rigby-Jones AE, Nolan JA, Priston MJ, Wright P, Sneyd R, Wolf AR, Pharmacokinetics of propofol infusion in critically ill neonates, infants, and children in an intensive care unit., Anesthesiology 2002; 97: 1393-400.).
• the influence of such physiological, anatomical and biochemical or genetic peculiarities on the course of anesthesia can only be insufficiently described with the device known from the prior art.
• the use of an open three-compartment model limits the flexibility to consider different patient conditions such as age-related differences in body composition, blood flow rates and rate of metabolism, obesity or pregnancy, etc.
• Lewitt et al. describes a physiology-based pharmacokinetic model for the simulation of propofol plasma pharmacokinetics after intravenous administration (Levitt DG, Schnider TW, Human physiologically based pharmacokinetic model for propofol, BMC Anesthesiol 2005 Apr 22; 5 (1): 4).
• the model provides a good description of the concentration-time course of propofol in the plasma of adult patients, but does not describe the extent to which the model calculable concentrations in the brain are effective in determining the time course of the effect of propofol.
• the applicability of this model is further limited by the fact that only the fat content of the patient on the basis of an empirical correlation equation and the propofol clearance are taken into account as individual parameters.
• the invention is based on the object of developing an improved device which enables an exact time distribution of propofol taking into account individual physiological, anatomical, biochemical and genetic factors of the patient.
• the invention therefore relates to a device in which a PBPK / PD model is used in order to optimize an optimal time course for the individual patient by iterative adaptation of either the concentration-time course in the brain or the pharmacodynamic effect-time course to determine a given temporal target profile.
• This optimized time course of administration then serves as the input function for a dosing device.
• a closed control loop which is clearly superior to the black box device mentioned in the prior art, which dispenses with the use of physiological knowledge.
• the essential feature of the invention is the combination of a physiology-based pharmacokinetic and / or pharmacodynamic model (PBPK / PD) with an automated dosing device such as an electronically controlled infusion pump.
• PBPK / PD models are advantageous over non-physiological compartment models because they are able to describe in detail the influence of individual physiological, anatomical, biochemical and genetic factors on pharmacokinetics and dynamics.
• FIG. 1 A schematic representation of the device according to the invention is shown in Figure 1.
• the main component is a PBPK / PD model (101), which describes a mammalian organism (especially human) and requires a number of different parameters as input variables:
• Substance-specific parameters of the anesthetic agent to be administered (102).
• Typical substance-specific parameters are e.g. physicochemical parameters such as lipophilicity, binding constant to human serum albumin and / or other plasma proteins, unbound plasma fraction, solubility in aqueous buffer solution or in intestinal fluid, size of the molecule (expressed by molecular weight or molar volume), hepatic and / or renal clearance, permeability coefficients, e.g. via artificial or biological membranes, and equilibrium distribution coefficients between plasma (or blood) and the various organs.
• physicochemical parameters such as lipophilicity, binding constant to human serum albumin and / or other plasma proteins, unbound plasma fraction, solubility in aqueous buffer solution or in intestinal fluid, size of the molecule (expressed by molecular weight or molar volume), hepatic and / or renal clearance, permeability coefficients, e.g. via artificial or biological membranes, and equilibrium distribution coefficients between plasma (or blood) and
• Species-specific physiological, anatomical, biochemical and / or genetic input parameters characteristic of the patient under consideration include, in particular, body weight, volume fractions of individual organs in the total body volume, blood flow rates of individual organs, water, fat and lipid content of the individual organs, as well as parameters that influence the expression and function of metabolically active enzymes (especially in the liver and intestine). or characterize the expression and function of proteins for the active transport of molecules across cell membranes.
• a target profile which indicates the desired concentration-time course of the anesthetic agent to be administered in the plasma, blood or directly on the biochemical target in the target organ, or the desired effect-time course ("TARGET profile", 105).
• TARGET profile a rectangular effect profile is sought with as steep flanks as possible, ie the desired anesthesia effect should be spontaneous, then remain as constant as possible over a defined period of time, and decay rapidly at the end of the treatment.
• the target profile can be either a simple temporal function Z (t) or alternatively or additionally given as a tolerance range (defined as an interval over a maximum value and a minimum value [ ZnUn (O .. Z 013x (I)]).
• the PBPK / PD model calculates the individual concentration-time profile or effect-time profile for the considered substance on the basis of the information from 1.) - 2.) ("IST Profile ", 106).
• the dosage profile is varied until the simulated concentration-time profile or effect-time profile agrees with the TARGET profile (107, 108).
• the temporal dosage profile is obtained which effects the desired concentration-time or effect-time profile for the substance under consideration in the individual patient or shows the slightest deviation from this.
• Numerical optimization methods include, for example, gradient methods, gradient-free methods, stochastic methods or evolutionary methods.
• the gradient methods the quasi-Newton or Newton method and in particular the interval box method are particularly preferred for the gradient-free methods.
• the stochastic methods particularly prefer the Monte Carlo method
• the method of genetic optimization represents a particularly preferred method Form of an evolutionary process.
• This dosage profile is used in the last step to control an automatic dosing device.
• the present invention thus relates to a device for the timed administration of the anesthetic propofol, characterized in that: a) a substance-dependent target profile, which indicates a desired concentration-time course in the brain or a desired effect time course,
• a dosing device is controlled on the basis of the result under c).
• the control of the dosing device may be useful not to make the control of the dosing device solely on the desired pharmacokinetic or pharmacodynamic target profile out, but an external measure, for example. to derive parameters derived from an electroencephalogram (EEG) as another input parameter.
• EEG electroencephalogram
• the depth of anesthesia is additionally monitored online by one or more suitable measuring probes and the measuring signals are integrated into the method as additional input variables.
• the control of the dosing device is then not controlled purely by the pharmacodynamic or pharmacokinetic time profile, but involves external measurement signals.
• the supply of an anesthetic can be increased if the measured depth of anesthesia falls below a critical value.
• a closed loop can be realized, which optimizes the temporal dosage of the anesthetic using real-time online measurements and physiological simulations.
• parameters measured using an electroencephalogram (EEG) such as the Bispectral Index (BIS) may be considered as online measurements.
• EEG electroencephalogram
• BIS Bispectral Index
• the response of the pharmacodynamic or pharmacokinetic profile known from physiological simulation to changes in the rate of application is used to readjust the rate of anesthetic delivery to the patient's needs indicated by the probe.
• only the signal of the measuring probe is briefly used for regulation if a critical condition exists (for example, if the patient threatens to wake up prematurely from the anesthetic).
• DE-A-10 345 837 has also described how biochemical and genetic information, such as expression data of metabolically active enzymes or active transporters, can be used to determine a dosage individually adapted to the patient.
• This simulation method in combination with a dosing device, enables the desired temporal dosage of propofol, taking into account individual physiological, anatomical, biochemical and genetic factors of the patient.
• the device according to the invention As a target group for the application of the device according to the invention are humans and mammals, including in particular livestock, breeding, laboratory, experimental and hobby animals in question. Most preferably, the method is used as an adjuvant for the therapeutic treatment of humans or for clinical trials in humans.
• the livestock and breeding animals include mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer and fur animals, e.g. Mink, chinchilla or raccoon.
• Laboratory and experimental animals include mice, rats, guinea pigs, hamsters, rabbits, dogs, cats, pigs and monkeys in all species, subspecies and breeds.
• Hobby animals include dogs and cats in particular.
• Electronically controlled dosing devices are, in particular, electronically controlled infusion pumps.
• the application example is based on simulations using the commercially available physiology-based pharmacokinetic model PK-Sim ® developed by Bayer Technology Services GmbH and the TIVA-Trainer published and available on the internet.
• the following values for propofol were used as substance-dependent input parameters in PK-Sim® (Table 1):
• Another important input is the clearance, ie the elimination rate of the substance.
• Propofol is metabolised in the liver.
• the activity of the metabolizing enzymes is known to be age-dependent.
• Figure 2 shows a fit (line) through experimental data (symbols) describing propofol clearance as a function of age. Utilizing the Create Individual function, the studies cited in Table 2 were simulated. Likewise, these cases were simulated with the Diprifusor TM software TTVA-Trainer and in the case of the pediatric study with the Paedforsor model.
• Figure 3 shows the predicted (lines) and experimental (symbols, data from Raoof AA, Van Obbergh LJ, Verbeeck RK, Propofol pharmacokinetics in children with biliary atresia, Br J Anesth 1995; 74: 46-9) Propofol concentrations in the blood after intravenous administration in children (mean age 1.9 years).
• Figure 4 shows the predicted (lines) and experimental (symbols, data from Saint-Maurice C, Cockshott ID, Douglas EJ, Richard MO, Harmey JL Pharmacokinetics of propofol in youn ' g children after a single dose., Br J Anaesth 1989; 63 (6): 667-70.) Propofol levels in the blood after intravenous administration in children (mean age 5.5 years).
• Fig. 5 shows the predicted (lines) and experimental (symbols, data from Valtonen M, Iisa Io E, Kanto J, Rosenberg P. Propofol as an induction agent in children: pain on injection and pharmacokinetics, Acta Anesthesiol Scand 1989, 33 (2): 152-5) Propofol concentrations in blood after intravenous administration in children (mean age 6.5 years).
• Figure 6 shows the predicted (lines) and experimental (symbols, data of Kanto J, Rosenberg P. Propofol in cesarean section, A pharmacokinetic and pharmacodynamic study, Methods and Findings in Experimental Clinical Pharmacology 1990, 12 (10): 707- l l.) Propofol concentrations in the blood after intravenous administration in pregnant women (mean age 27.1 years).
• Figure 7 shows the predicted (lines) and experimental (symbols, data from Mertens MJ, Olofsen E, Burm AG, Bovill JG, Vuyk J. Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics .Anesthesiology 2004; 4): 795-805.) Propofol levels in the blood after intravenous administration in young men (mean age 24 years).
• Figure 8 shows the predicted (lines) and experimental (symbols, data from Ickx B, Cockshott ID, Barvais L, Byttebier G, De PL, Vandesteene A et al., Propofol infusion for induction and maintenance of anesthesia in patients with end-stage renal Br i Anesth 1998; 81 (6): 854-60.) Propofol levels in the blood after intravenous administration in adults (mean age 45.2 years).
• the mean relative deviation (MRD) was calculated in each case for the curves predicted by PK-Sim® and by TFVA trainer according to the formula:
• Figures 3 to 8 and the calculated MRD values from Table 3 show that the individual concentration-time courses of propofol can be better predicted with the physiology-based model in all cases than with the conventional open three-compartment models.
• the relative standard deviation of these concentration values was determined.
• the relative standard deviation of drug concentrations in the brain at the time of loss of consciousness was 27% in the normal weight population.
• TrVA-Trainer model the relative standard deviation of the effect compartment concentration in this population was 32%.
• the standard deviation obtained with PK-Sim® was marginally larger than in the normal-weight population (41%).
• the standard deviation in the overweight population of the TIVA-Trainer was significantly higher at 93%.
• the time of the reawakening is also correlated again with the concentration of propofol when discharging anesthesia. It is to be expected that induction and discharge of anesthesia are associated with very similar drug concentrations in the brain. As shown in Table 4, the drug levels predicted by PK-Sim® in the brain at the time of recovery (3.4 mg / L) are very well consistent with drug levels in the brain at the time of loss of consciousness. These threshold levels of brain concentration are in the absolute range of 2.2 to 4.0 mg / L. The concentration levels for the effect compartment calculated by the TIVA trainer were 2.2 for the time the consciousness was recovered and 1.0 to 1.6 for the simulated loss of consciousness, which is a significant mismatch between the two values.
• PK-Sim® was able to predict very accurately the time of the minimum BIS value (relative deviation + 8.3 s), while the predictive model of the diffrusor model was almost a factor of 2 off.
• Table 4 Pharmacodynamic endpoints predicted by PK-Sim ® and Diprifusor
• a target profile Z (t) for propofol in the brain can be described.
• Z m1n (O and Z max (t)) which must not be exceeded or fallen short of during the duration of an anesthesia If the patient falls below this threshold, the patient may be woken up during the procedure, while in case of exceeding this undesirable side effects are not excluded can.
• a desired profile Z (t) for example, a rectangular profile for the drug concentration in the brain with a plateau value of 3.5 mg / L propofol during the anesthetic period (t N ⁇ kose ) makes sense.
• the upper and lower limits are 3.0 mg / L and 4.0 mg / L in the brain, respectively.
• the time t L oc defines the desired beginning of the anesthesia. This results in the following function for the target profile Z (t): 0 t ⁇ t LOC
• a target profile for the BIS value can also be specified directly.
• the iterative rate of infusion i. H. the intravenously administered dose per time interval varies.
• the stepwise approach is usefully chosen so that it is adapted to the distribution and elimination kinetics of the substance.
• the amount applied in the corresponding time step is varied until, overall, the actual profile within the tolerance range coincides with the nominal profile.
• Suitable numerical optimization methods include, for example, gradient methods, in particular Quasi-Newton or Newton methods, as well as gradient-free methods such as interval hunching and stochastic methods such as Monte Carlo methods.
• Figure 1 Schematic representation of the device for the timed dosing of anesthetics.
• Figure 3 Predictive (lines) and experimental (symbols, data from Raoof et al.) Propofol concentrations in the blood after intravenous administration in children (mean age 1.9 years).
• the solid line shows the concentrations calculated by PK-Sim® and the dashed line the concentrations calculated by the TTVA trainer.
• Figure 4 Predictive (lines) and experimental (symbols, data from Saint-Maurice et al.) Propofol concentrations in the blood after intravenous administration in children (mean age 5.5 years).
• the solid line shows the concentrations calculated by PK-Sim® and the dashed line the concentrations calculated by the TIVA trainer.
• Figure 5 Predictive (lines) and experimental (symbols, data from Valtonen et al.) Propofol concentrations in the blood after intravenous administration in children
• the solid line shows the concentrations calculated by PK-Sim® and " the dashed line the concentrations calculated by the TIVA trainer.
• Figure 6 Predictive (lines) and experimental (symbols, data from Kanto et al.) Propofol concentrations in the blood after intravenous administration in pregnant women (mean age 27.1 years).
• the solid line shows that of PK
• Figure 7 Predictive (lines) and experimental (symbols, data from Mertens et al.) Propofol concentrations in the blood after intravenous administration in young men (mean age 24 years).
• the solid line shows the concentrations calculated by PK-Sim® and the dashed line the concentrations calculated by the TIVA trainer.
• Figure 8 Predictive (lines) and experimental (symbols, data from Ickx et al.) Propofol concentrations in the blood after intravenous administration in adults (mean age 45.2 years).
• the solid line shows the concentrations calculated by PK-Sim® and the dashed line the concentrations calculated by the TIVA trainer.

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medical Informatics (AREA)
• Biomedical Technology (AREA)
• Epidemiology (AREA)
• Primary Health Care (AREA)
• Medicinal Chemistry (AREA)
• Anesthesiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Databases & Information Systems (AREA)
• Vascular Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Pathology (AREA)
• Heart & Thoracic Surgery (AREA)
• Data Mining & Analysis (AREA)
• Hematology (AREA)
• Pharmacology & Pharmacy (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Infusion, Injection, And Reservoir Apparatuses (AREA)
• Measuring And Recording Apparatus For Diagnosis (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=36940350

Family Applications (1)

Country Status (7)

Families Citing this family (48)

Family Cites Families (17)

• 2005
  • 2005-06-17 DE DE102005028080A patent/DE102005028080A1/de not_active Withdrawn
• 2006
  • 2006-06-03 JP JP2008516175A patent/JP5033794B2/ja not_active Expired - Fee Related
  • 2006-06-03 WO PCT/EP2006/005340 patent/WO2006133825A1/de active Application Filing
  • 2006-06-03 AU AU2006257418A patent/AU2006257418B2/en not_active Ceased
  • 2006-06-03 US US11/917,452 patent/US8038645B2/en not_active Expired - Fee Related
  • 2006-06-03 CA CA002612215A patent/CA2612215A1/en not_active Abandoned
  • 2006-06-03 EP EP06743110A patent/EP1904940A1/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events