DOSAGE CONTROL FOR DRUG DELIVERY SYSTEM

altA method for delivering intravenous drugs to a patient comprising programming a drug delivery system, including a controller and an infusion pump, with a maintenance rate or a loading dose for a drug and causing the drug delivery system to (a) calculate a loading dose based on the maintenance rate or a maintenance rate based on the loading dose, (b) administer the loading dose of the drug to the patient to rapidly achieve a desired level of effect, and (c) administer the drug at a first maintenance rate to maintain the level of effect

 

Inventors: MARTIN; James F.; (Lenanon, OH)

Serial No.: 038841
Series Code: 13
Filed: March 2, 2011
Current U.S. Class: 604/500; 604/151
Class at Publication: 604/500; 604/151
International Class: A61M 21/00 20060101 A61M021/00; A61M 5/168 20060101 A61M005/168

 

Claims


1. A method for sedating a patient comprising: (a) selecting a first maintenance rate or an initial loading dose for a sedation drug; (b) calculating an initial loading dose based on the maintenance rate or a maintenance rate based on the initial loading dose; (c) administering the initial loading dose of the sedation drug to the patient to achieve a desired level of sedation; (d) administering the sedation drug at a first maintenance rate to maintain the level of sedation; (e) selecting a second maintenance rate to adjust the level of sedation; (f) calculating an incremental loading dose based on a cumulative loading dose and the second maintenance rate; (g) calculating the cumulative loading dose administered to the patient based on the formula: LD_cum.sub.x+1=LD_cum.sub.x+amount of LD delivered in sample; (h) administering the incremental loading dose to the patient to achieve a second level of sedation; and (i) administering the sedation drug at the second maintenance rate to maintain a second level of sedation.

2. The method of claim 1 wherein the step of administering the loading dose is performed using an infusion pump at an infusion rate approximately equal to the maximum infusion rate of the pump.

3. The method of claim 1 wherein the step of administering the loading dose is conducted by administering the loading dose over a predetermined period.

4. The method of claim 1 wherein the second maintenance rate is greater than the first maintenance rate.

5. The method of claim 1 wherein the method includes the step of monitoring the patient's level of sedation based on patient's response to an automated responsiveness monitoring system (ARM).

6. The method of claim 5 wherein the step of monitoring the level of sedation includes sending a request using the automated responsiveness monitoring system (ARM) to the patient to generate a response, wherein the request is a query regarding the patient's comfort level.

7. A drug delivery system that delivers a loading dose and a maintenance rate of a drug to a patient, the system including an infusion pump and a controller, the controller being programmed such that the system performs the steps of: (a) calculating a loading dose based on the maintenance rate or a maintenance rate based on the loading dose; (b) administering the loading dose to the patient to achieve a desired level of effect; and (c) administering the drug at a first maintenance rate to maintain the level of sedation.

8. The drug delivery system of claim 7 wherein the step of calculating a loading dose based on the maintenance rate or a maintenance rate based on the loading dose is based on a formula that correlates the maintenance rate and the loading dose recommended by the drug supplier.

9. The drug delivery system of claim 8 wherein the formula is based upon a linear interpolation of the maximum recommended loading dose and the maximum recommended maintenance rate.

10. The drug delivery system of claim 7 wherein the controller includes a setting to administer the loading dose by operating the infusion pump at an infusion rate approximately equal to the maximum infusion rate of the pump.

11. The drug delivery system of claim 7 wherein the controller includes a setting to administer the loading dose by administering the loading dose over a predetermined period.

12. The drug delivery system of claim 7 wherein the drug delivery system tracks the cumulative loading dose administered to the patient, wherein the cumulative loading dose is calculated based on the formula: LD_cum.sub.x=LD_cum.sub.x-1+amount of LD currently delivered in sample x

13. The drug delivery system of claim 7 wherein the controller is programmed with a second maintenance rate whereupon the system: (a) calculates an incremental loading dose for the drug based on the second maintenance rate (b) administers the incremental loading dose to the patient to rapidly achieve the new desired level of effect; and (c) administers the drug at the second maintenance rate to maintain the new level of effect.

14. The drug delivery system of claim 9 wherein the controller is programmed to calculate the loading dose based on the formula: LD=0.5*W*(MR/75) where, LD=Loading Dose (mg), MR=Maintenance Rate (.mu.g/kg/min), W=Weight (kg) of the patient.

15. The drug delivery system of claim 9 wherein the controller is programmed to calculate the incremental loading dose based on the formula: Incremental LD=0.5*W*(MR_new/75)-LD_cum

16. The drug delivery system of claim 13 wherein the controller is programmed to administer the incremental loading dose over a predetermined period.

17. The drug delivery system of claim 7 where the infusion pump delivers the drug at an infusion rate that can be set to zero for a period of time.

18. The drug delivery system of claim 17 wherein the controller is programmed to calculate the zero period of time based on the incremental loading dose.

19. The drug delivery system of claim 18 wherein the zero time period is calculated using the formula: Zero_time=60*1000*LD/(MR*W)

20. The drug delivery system of claim 7 wherein the controller includes a setting to deliver a transient bolus of the drug to temporarily increase in the patient's level of effect.

21. The drug delivery system of claim 7 wherein the system includes sensors for sensing the physiology of the patient and the controller is programmed to discontinue the step of administering the drug if adverse physiology or an adverse trend in physiology is detected.

22. The drug delivery system of claim 21 wherein the controller is programmed to calculate a maintenance rate reduction by calculating the apparent maintenance rate at the time the adverse physiology or trend has cleared (physiology returns to normal), based on the formula: MR_apparent=75*LD_cum/(0.5*W)

23. The drug delivery system of claim 7 wherein the system further includes an automated response monitoring system (ARM).

24. The drug delivery system of claim 23 wherein the system further includes a patient response input.
Description


CROSS REFERENCE TO RELATED PATENT APPLICATION

[0001] This is a continuation of U.S. patent application Ser. No. 11/695,775, filed on Apr. 3, 2007, which is a continuation of U.S. patent application Ser. No. 10/886,255, filed on Jul. 7, 2004, now abandoned.

FIELD OF THE INVENTION

[0002] The present invention relates generally to drug delivery systems, and more particularly to a method of calculating a drug infusion profile for a drug delivery system. While the invention can be used in administering a variety of intravenous drugs it is particularly useful as an anesthetic delivery system.

BACKGROUND OF THE INVENTION

[0003] Three conditions or objectives control the administration of an anesthetic, namely, to rapidly produce the desired pharmacologic effect (hypnosis, analgesia, etc.); to maintain the desired effect throughout the medical procedure; and to enable the patient to recover quickly from the effect following completion of the procedure.

[0004] In order to achieve the objective of rapidly inducing the desired anesthetic effect, the anesthesiologist typically delivers a so called "Loading Dose." A Loading Dose is a bolus (mg/kg, mg, etc.) of drug that rapidly brings the patient to a desired level of effect. In order to maintain the level of effect the anesthesiologist often uses an infusion pump to deliver a so called "Maintenance Rate." A Maintenance Rate is a constant infusion rate (.mu.g/kg/min, mg/min, etc.) required to maintain the patient at a certain target, in this embodiment anesthetic, effect. The anesthesiologist may have to titrate this Maintenance Rate during the procedure as the patient's anesthetic needs change. A method that allows for rapidly adjusting the patient's level of effect is desired. Finally, in order to enable the patient to recover quickly from the anesthetic following completion of the procedure, the anesthesiologist attempts to deliver as little drug as needed. This can include tapering down the Maintenance Rate prior to the end of the procedure.

[0005] The term "anesthesia" is used herein to refer to the continuum of hypnosis and analgesia, achieved via anesthetic drugs, from anxiolysis through general anesthesia. In producing a level of anesthesia known as conscious sedation, as practiced by endoscopists, the anesthetic(s) is typically delivered through frequent boluses. This technique results in varying depths of anesthesia throughout the procedure. At times the patient may be so heavily anesthetized as to be classified in general anesthesia. At other times the patient may be under-anesthetized and exhibit pain and agitation. A patient responding to pain is uncooperative, making the procedure more difficult. As a result, the clinician tends to err on the over-anesthetized side. In addition to placing the patient at greater risk for adverse events, over-anesthetizing causes the patient's recovery from anesthesia to be much longer. Accordingly, a method is desired that enables the clinician to control the level of anesthesia without over- or under-anesthetizing the patient.

[0006] The term "sedation drug" is used herein to refer to the classes of drugs employed by anesthesiologists in inducing sedation including hypnotics and analgesics. Propofol and remifentanil are preferred drugs for sedation, principally due to their rapid onset and offset. However, this rapid action presents additional concerns for someone using an intermittent bolus technique, as typically done by non-anesthesiologists. With a rapid onset/offset more frequent boluses will be required. Consequently, anesthesiologists often use infusion pumps to continuously deliver these rapid action sedation drugs. However, non-anesthesiologists are not familiar with pharmacokinetic (PK) principals, and will have difficulty determining a Loading Dose/Maintenance Rate combination that will both rapidly achieve and maintain the desired level of anesthesia. The Anesthetic Delivery System (ADS) is intended to enable a non-anesthesiologist to safely and effectively use these rapid action anesthetic agents typically reserved for use by anesthesiologists.

[0007] What is desired is an algorithm that will allow the clinician to program an ADS with a desired maintenance rate, selected by the clinician to maintain a desired level of anesthesia, and then the ADS automatically calculates the appropriate sized loading dose based on the pharmacokinetics of the chosen sedation drug. The loading dose is then delivered by the ADS to rapidly achieve the level of sedation, immediately followed by a constant infusion of the sedation drug at the maintenance rate, to maintain the level of anesthesia. Moreover, a method is desired where the patient's level of anesthesia is rapidly adjusted, each time the clinician changes the maintenance rate, in response to the patient's changing anesthetic needs. Specifically, what is needed is an ADS that integrates the initiation and maintenance of anesthesia in an equation so that the appropriate sized loading dose may be calculated and administered to rapidly bring the patient's depth of anesthesia to a level maintained by the programmed maintenance rate. Further, when a change in the maintenance rate is requested, the dosage controller (DC) can calculate an incremental loading dose to rapidly achieve the new level of anesthesia.

SUMMARY OF THE INVENTION

[0008] In one embodiment, the invention provides a method of drug infusion for maintaining or rapidly adjusting a patient's level of anesthesia comprising programming an automated drug delivery system with a maintenance rate (MR); causing the drug delivery system to calculate the loading dose (LD) using a formula that relates loading dose and maintenance rate; the drug delivery system infusing the loading dose into patient to achieve a desired level of anesthesia and administering the drug at the maintenance rate to maintain the level of anesthesia.

[0009] In another embodiment, the invention provides a method of drug infusion for maintaining or rapidly adjusting a patient's level of anesthesia comprising the clinician programming an automated drug delivery system with a loading dose (LD); causing the drug delivery system to calculate the maintenance rate (MR) using a formula that relates loading dose and maintenance rate; the drug delivery system infusing the loading dose into the patient to achieve a level of anesthesia and administering the drug at the maintenance rate to maintain the level of anesthesia.

[0010] In a further embodiment, the level of anesthesia is rapidly adjusted when the clinician programs a new maintenance rate, by a method that further comprises: calculating the cumulative loading dose based on the drug already administered to the patient; calculating a new loading dose based on the cumulative loading dose and a new maintenance rate based on a formula relating loading dose and maintenance rate; the ADS infusing the new loading dose into patient to achieve the new level of anesthesia and the administering the drug at the desired new maintenance rate to maintain the new level of anesthesia.

[0011] Still a further embodiment is a drug delivery system that includes an infusion pump and a controller and is programmed to control infusion as described herein. In one embodiment, the system includes sensors for monitoring patient physiology and can be programmed to discontinue administering the drug if adverse physiology or trends are detected.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 is a drawing of the Automated Response System (ARM) utilized in an embodiment of the invention.

[0013] FIG. 2 is a collection of flow charts (FIGS. 2A-2F) for a DC program useful in accordance with an embodiment of the invention.

[0014] FIGS. 3 and 4 are graphs illustrating the determination of a ramped infusion rate for a loading dose that culminates in the maintenance rate.

DETAILED DESCRIPTION OF THE INVENTION

[0015] For the purposes of illustration, the invention is explained using the delivery of propofol to achieve and maintain a level of anesthesia referred to as conscious sedation. However, the invention can be applied to any intravenous drug where it is appropriate to deliver a loading dose followed by a maintenance infusion. The equations will be adjusted for different pharmacokinetics (loading dose/maintenance rate relationships) for these other drugs. Examples of classes of drugs in addition to sedation drugs that can be administered in accordance with the invention are antibiotics, pain management drugs, cardiovascular drugs, anticancer drugs, and others.

A. Initiation of Sedation

[0016] An anesthetic drug such as propofol provides labeling recommendations for initiating sedation (loading dose) -0.0 to 0.5 mg/kg, and infusion rates for maintaining the patient's level of sedation (maintenance rate) -0.0 to 75 .mu.g/kg/min. DC is designed to correlate these two ranges, such that a clinician simply enters a maintenance rate (MR) and DC will calculate the appropriate loading dose (LD) with the following equation in the case of propofol:

LD=0.5*W*(MR/75)

[0017] where, [0018] LD=loading lose (mg), [0019] MR=maintenance rate (.mu.g/kg/min), [0020] W=weight (kg) of the patient [0021] 0.5=0.5 mg/kg [0022] 75=75 .mu.g/kg/min.

[0023] For other drugs, and application, similar correlations can be developed. While these correlations will often be defined in terms of the weight of the patient, this does not have to be true for all cases. Some drugs may have dosages that are less dependent or essentially independent of patient weight for typical patients. The equation that has been developed for propofol above is based on the maximum loading dose (0.5 mg/kg) recommended for the drug and the therapy (e.g., conscious sedation) in which the drug is used and the maximum maintenance rate (75 .mu.g/kg/min). In this case the formula is a linear proportion or linear interpolation. The clinician may select a maintenance rate corresponding to the level of anesthesia he desires to achieve, e.g., ASA guidelines are drafted in terms of mild, moderate and deep anesthesia and based on the ratio of that maintenance rate to the maximum maintenance rate recommended for that application of the drug, a loading dose is determined. Thus, in accordance with certain embodiments of the invention, the equation relating loading dose to maintenance rate will represent a linear proportion or interpolation based on the loading dose and maintenance rate ranges suggested by the supplier and still more specifically based on the maximum loading dose and maintenance rate suggested by the supplier. These ranges may be therapy specific, for example, a different proportion or interpolation based on the drug label's recommended loading dose and maintenance rate for that therapy would be used if general anesthesia as opposed to conscious sedation was the objective. The loading dose calculation flow chart is provided in FIG. 2F where the calculation based on the maximum label dose is shown as program step 260.

[0024] After the loading dose (LD) has been calculated, the anesthetic delivery system (ADS) will automatically deliver it, prior to starting the maintenance rate (MR). As shown in FIG. 2B, the loading dose can be administered in a rapid induction model or a controlled induction model (see program determination 262).

[0025] 1. Rapid Induction

[0026] In one embodiment illustrated in program step 222 in FIG. 2B, the ADS can deliver the LD at the maximum pump rate. For the purpose of illustration, 999 ml/hr will be used as the maximum pump rate. DC first calculates the time required (seconds) to deliver the LD at 999 ml/hr:

LD_time=3600*LD/(10*999)

[0027] where 3600 is the conversion from hours to seconds (sec/hr) and 10 is the concentration of the propofol solution (mg/ml). The LD_time is then converted into sampling intervals. For the purpose of illustration only, a sampling interval of 1.5 seconds will be used:

LD_intervals=LD_Time/1.5

[0028] If the number of LD_intervals is not an integer, then DC calculates the infusion rate (ml/hr) for the last interval (program step 228) to deliver the remainder of the LD using the equation:

IR.sub.--LD_remain=999*Interval_remain+MR_ml/hr*(1-Interval_remain)

[0029] where,

MR_ml/hr=MR*W/166.67=Maintenance Rate in ml/hr

Interval_remain=LD_intervals-INTEGER(LD_intervals)

[0030] Note that the 166.67 is the conversion based on 60 min/hr, and 1,000 .mu.g/mg, and 10 mg/ml (propofol concentration).

[0031] The ADS then delivers the loading dose for INTEGER(LD_Intervals) at a pump rate 999 ml/hr, and then delivers at IR_LD_remain for one interval. This is shown if FIG. 2B in program steps 226 and 228. Immediately following the completion of the LD, the ADS starts delivery of the MR (actually at a pump rate of MR_ml/hr).

[0032] 2. Controlled Induction

[0033] In an alternative embodiment illustrated in FIG. 2B at program step 224, the ADS can deliver the LD over a specified period of time, with a decreasing ramp that culminates at the maintenance rate. For the purpose of illustration, 3 minutes (180 seconds) will be used as the Controlled Induction time. First, DC calculates the infusion rate (.mu.g/kg/min) required if the LD were delivered at a constant rate over those 3 minutes:

Temp_rate=1000*LD/(W*3)

[0034] where, 1000 is conversion from mg to ng.

[0035] As shown in FIG. 3, the area of the rectangle (dashed line in FIG. 3) defined by the Controlled Induction period (180 seconds) and the Temp_rate equals the LD. For this embodiment, the objective is to calculate a ramp, such that the area under the ramp is equal to the area of the rectangle defined by the Temp_rate. This is accomplished with basic geometry. First, since the ramp terminates into the Maintenance Rate (dotted line at 75 .mu.g/kg/min in FIG. 3) at the end of the Controlled Induction period, the area under the Maintenance Rate can be ignored for the following analysis--so the focus can be on the areas above the MR. Then, if the ramp is such that the height of the ramp is equal to two times the height of the rectangle (above the MR) then the area under the ramp is equal to the area under the rectangle. This is illustrated in FIG. 3: A1=A2, therefore the area of the triangle equals the area of the rectangle.

[0036] The DC first calculates the difference (Delta) between the Temp_Rate and the MR:

Delta=Temp_rate-MR

[0037] then in this example, the starting rate (.mu.g/kg/min) for the ramp would be

2*Delta

[0038] and the slope (.mu.g/kg/min/min) of the ramp in this example would be

Slope=2*Delta/3

[0039] where 3 is the induction period. However, this assumes a continuous ramp. The DC ramp is actually a series of decreasing steps (each step defined by the sampling interval, which is 1.5 seconds in this illustration). The area under this "staircase" must equal the area under the ramp, in order for the LD to be correct. The same geometrical principal applied above applies here as well, and is illustrated in FIG. 4. If the height of each step is equal to the average height of the ramp over the step interval the areas will be the same.

[0040] Therefore, the starting rate (.mu.g/kg/min) for the ramp is more correctly expressed as:

Start.sub.--IR=MR+2*Delta-(Slope/2)/40

[0041] where 40 is the number of samples taken over a minute (1.5 second intervals)--converting the slope from "per minute" to "per interval."

[0042] The ADS delivers the LD starting at Start_IR and then ramps down the infusion rate, each sample, over the next 3 minutes:

LD.sub.--IR=Start.sub.--IR-Slope*Interval_count/40

Interval_count.sub.x=Interval_count.sub.x-1+1

[0043] where, Interval_count is a counter tracking the progression of the 120 samples in the 3 minute period. At the end of the 3 minutes the infusion rate will be equal to the MR selected by the user, and the ADS will continue to deliver the MR.

[0044] It is important to note that all the calculations are in .mu.g/kg/min, therefore before sending the rate to the pump it must be converted into ml/hr. The standard equation for converting from .mu.g/kg/min to ml/hr is:

IR_ml/hr=IR*W/166.67

[0045] In another embodiment for the Controlled Induction, DC could simply deliver the Temp_Rate over the entire time period, then switch to the Maintenance Rate. This embodiment is illustrated in FIG. 2B of the flow chart. In the illustrated embodiment, the system gives the clinician the option in program step 220 of selecting between the rapid induction mode 222 or the controlled induction mode 224.

[0046] The method described above basically portrays how anesthesiologists, who are trained in pharmacokinetic principals, sedate a patient. The DC is advantageous because it automatically correlates the loading dose with the maintenance rate (or vice versa) so that only one variable is needed to compute the other. For example, whereas in the prior art, the physician needed a value for both the loading dose and the maintenance rate in order to rapidly initiate and maintain sedation, a ADS using the DC is able to calculate the appropriate loading dose based on a given maintenance rate. Thus, by entering the desired maintenance rate for the patient, DC automatically calculates the loading dose needed to rapidly bring the patient's level of sedation to the selected maintenance rate. The loading dose is administered followed by the constant infusion at the specified maintenance rate.

[0047] Conversely, the DC can also calculate a maintenance rate based on a given loading dose value.

MR=75*LD/(0.5*W)

B. Adjusting Level of Sedation

[0048] DC also allows for rapid adjustment to a new level of sedation when the clinician programs a new maintenance rate. In prior methods of drug infusion, if an anesthesiologist intra-procedurally decides to change the patient's level of sedation, he will typically adjust only the infusion rate, and not deliver another loading dose. This results in a slower adjustment from the present level of sedation to the new level of sedation. However, DC can calculate an incremental loading dose for each change in maintenance rate. This results in a significantly quicker adjustment because delivering an additional bolus rapidly brings the patient to the new level of sedation.

[0049] 1. Incremental and Cumulative Loading Dose

[0050] In accordance with the invention, a correlation is established between loading dose and maintenance rate. Based upon this correlation, by tracking the accumulated loading dose, the ADS can quickly define a bolus or incremental loading dose that will rapidly produce a level of sedation that is consistent with the new maintenance rate. The clinician programs changes in the level of sedation he or she desires by inputting a new maintenance rate that the clinician associates with the desired level of sedation. Each time a maintenance rate change is requested, DC will calculate the loading dose required for the new maintenance rate based on the equation above and then subtract the total loading doses previously given (cumulative loading dose-LD_cum) as shown in FIG. 2F step 262 to compute the incremental loading dose value to be administered to the patient.

Incremental LD=0.5*W*(MR_new/75)-LD_cum

[0051] Before starting the new maintenance rate, the ADS will deliver this "incremental" loading dose to rapidly bring the patient from the present level of sedation to the new level, and then maintain this new level of sedation at the new maintenance rate.

[0052] The Cumulative Loading Dose may be computed as shown in FIG. 2E by the following formula:

LD_cum.sub.x=LD_cum.sub.x-1+amount of LD delivered during sample

[0053] Thus, the loading dose needed to rapidly increase the patient from the present level of sedation to the new level of sedation, i.e. the incremental loading dose, is calculated by calculating an initiation loading dose for the new maintenance rate and then subtracting the cumulative loading dose already delivered to the patient as shown in FIG. 2F, step 262. FIG. 2E illustrates the calculation of the cumulative loading dose. In the illustration the cumulative loading dose is adjusted to add the amount of loading dose added during a sample interval. Calculation of the cumulative loading dose when the addition of the incremental loading dose is made by the rapid induction method is shown at program step 252 in FIG. 2E. Alternatively, this addition can occur using the controlled induction as shown in program step 250 in FIG. 2E. When the loading dose is negative, the cumulative loading dose is reduced as shown at 254.

[0054] For the purpose of illustration, assume that to achieve a level of sedation corresponding to maintenance rate of 50 .mu.g/kg/min requires an initiation loading dose of 0.33 mg/kg, and to achieve a level of sedation corresponding to maintenance rate of 75 .mu.g/kg/min requires an initiation loading dose of 0.50 mg/kg. When the drug is being administered at a current maintenance rate of 50 .mu.g/kg/min and the physician desires to increase the patient's level of sedation with a maintenance rate of 75 .mu.g/kg/min, DC would calculate an incremental loading dose of 0.50-0.33=0.17 to bring the patient to a level of sedation corresponding to the new maintenance rate of 75 .mu.g/kg/min. Essentially, the incremental loading dose required to bring the patient to the level of sedation corresponding to new maintenance rate is calculated by taking the difference between the initiation loading dose required to bring a patient to a specified maintenance rate (e.g. LD=0.50 mg/kg for MR=75 .mu.g/kg/min) and the cumulative loading dose already administered to the patient (present MR=50 .mu.g/kg/min, LD was 0.33 mg/kg). Thus, to bring the patient from MR=50 to MR=75, the cumulative LD administered to the patient for MR=50 (0.33 mg/kg) is subtracted from the initiation LD for MR=75 (0.50 mg/kg) to get the incremental loading dose of 0.17 mg/kg. Accordingly, an incremental loading dose of 0.17 should be given to increase the patient from the present level of sedation to the new level of sedation. The new LD.sub.cum would then be 0.50 mg/kg which would be used to calculate a new incremental loading dose if another new maintenance rate is desired.

[0055] The "administration" of the incremental loading dose during a procedure when a physician decides to increase the maintenance rate, differs from when a physician decides to decrease the present maintenance rate as further described below.

[0056] 2. Increase in Maintenance Rate: Rapid Induction

[0057] During the procedure, the physician may determine that the patient is under-sedated and increase the maintenance rate. In order to rapidly bring the patient's level of sedation to the new level of sedation, an incremental loading dose will be delivered to the patient.

[0058] In the Rapid Induction embodiment, the ADS will deliver the LD as quickly as possible, setting the pump rate to a maximum rate (e.g., 999 ml/hr) until the LD is delivered. However, unlike the initiation LD, in this case DC must deliver the LD on top of an existing MR and the existing infusion rate must be accounted for in the calculation of the LD time.

[0059] The formula to determine the length of time to deliver the LD at 999 ml/hr is:

LD_time=3600*LD/(10*(999-MR_ml/hr))

[0060] where MR_ml/hr=MR*W/166.67, and MR is not the new maintenance rate, but it is the existing maintenance rate, prior to the change. At the end of the LD, once the ADS starts delivering the new maintenance rate (MR_new), the variable will be reset. This is illustrated in FIG. 2F, at step 268. [0061] LD_time is converted into intervals (again using 1.5 seconds for this illustration):

[0061] LD_intervals=LD_time/1.5

[0062] Again, if LD_intervals is not an integer, DC must calculate the infusion rate required to deliver the remainder of the LD during the next sample interval:

IR.sub.--LD_remain=999*Interval_remain+MR_new_ml/hr*(1-Interval_remain)

[0063] where,

Interval_remain=LD_intervals-INTEGER(LD_intervals)

[0064] and MR_new_ml/hr is the new maintenance rate converted to ml/hr.

[0065] The ADS will deliver the loading dose at a pump rate of 999 ml/hr for INTEGER(LD_intervals) and then at an infusion rate of IR_LD_remain for one sample. After delivering the LD the ADS will set MR to MR_new, and begin delivery of the new maintenance rate.

[0066] These equations are basically identical to the equations for the initial Loading Dose delivery. If at start up both LD_cum and MR are set to zero, and the initial maintenance rate is treated as MR_new, then the same equation can be used for all Rapid Induction maintenance rate increases.

[0067] 3. Increase in Maintenance Rate: Controlled Induction

[0068] In the Controlled Induction embodiment the ADS will deliver the LD over the specified time period (3 minutes for illustration) on top of the existing MR. See step 269 in FIG. 2F. As with an initiation LD, DC calculates infusion rate (.mu.g/kg/min) required as if the LD is to be delivered at a constant rate:

Temp_rate=1000*LD/(W*3)+MR

[0069] Again the maintenance rate value is not the new maintenance rate (MR_new), but the rate prior to changing the maintenance rate. In this way, the loading dose is being administered on top of the existing maintenance rate.

[0070] DC then calculates the difference between this Temp_Rate and the MR_new:

Delta=Temp_rate-MR_new

[0071] The starting rate (.mu.g/kg/min) for the ramp is then:

Start.sub.--IR=MR_new+2*Delta-(Slope/2)40

[0072] and the slope of the ramp (.mu.g/kg/min/min) is:

Slope=2*Delta/3

[0073] The ADS delivers the LD starting at Start_IR and then ramps down the infusion rate, each sample, over the next 3 minutes:

LD.sub.--IR=Start.sub.--IR-Slope*Interval_count/40

Interval_count.sub.x=Interval_count.sub.x-1+1

[0074] where, Interval_count is a counter tracking the progression of the 120 samples in the 3 minute period. At the end of the 3 minutes the infusion rate will be equal to the MR_new, and DC will set MR=MR_new and continue to deliver the new maintenance rate.

[0075] These equations are similar to the equations for the initial Loading Dose delivery. If at start up both LD_cum and MR are set to equal zero, and the initial Maintenance Rate is set as MR_new then the same equation can be used for all Three Minute Induction Maintenance Rate increases.

[0076] In an alternative embodiment the incremental LD can delivered at a constant rate over the "controlled induction" period.

[0077] 4. Decrease in Maintenance Rate

[0078] If the maintenance rate is decreased (e.g., if the clinician feels the patient is over-sedated) the incremental loading dose will be negative. However, it is not possible to withdraw drugs from the patient. Calculation of a negative loading dose is shown in FIG. 2C. To simulate a negative loading dose, the DC calculates the period of time it would take to deliver that negative dose at the existing maintenance rate based on the formula:

Zero_time=60*1000*LD/(MR*W)

[0079] where, 1000 is a conversion from mg to .mu.g, 60 is conversion from minutes to seconds, and MR is the existing maintenance rate prior to the change, not the new maintenance rate (MR_new). This is shown in FIG. 2F at program step 266. The cumulative loading dose is also decreased as shown in program step 254 in FIG. 2E.

[0080] This time is converted into sampling intervals. For the purpose of illustration a sampling interval of 1.5 seconds will be used:

Zero_intervals=Zero_time/1.5

[0081] Again, if Zero_intervals is not an integer, DC calculates the infusion rate required to deliver the remainder of the LD during the last sample:

IR_zero_remain=MR_new_ml/hr*(1-Interval_remain)

[0082] where,

Interval_remain=Zero_intervals-INT(Zero_intervals)

[0083] The ADS will stop delivery of propofol for INT(Zero_intervals) and then begin infusing at an infusion rate of IR_zero_remain for one sample. After completing the LD, the ADS will set the maintenance rate to MR_new, and begin delivery of the new maintenance rate.

C. Intra-Procedure Bolus of Propofol

[0084] During the procedure the physician may decide that a transient increase i C. Intra/p> cedure [00us of ese ofol Te; t0pe is converet MR=M//(MRred to deli t0pe is converet MR=M//(Mse i C.gin i,into 7p interval ohese eq0ADS will senance rad= rate interus of Propohat a transient increase i C. Intra/p> ry. n in FIG. will be used: C. Intra-Procedure Bolus odurent from the present level ofprogn biangc4daserva; insime/1.5

IR_zero_remain=MR_new_m samd:<

aintenanfance rad= r3)iw, anging the maintenance rate increasp existing1f Controllaspbw maintenanc C.g

e LD on l"e ras1 inaa]6 rateF Controllaspbw maintbtracted fr a]6eret MRl forvt MRlaspbw_inte is "ltenaof sf stransient increase i C. Intra/p> cedure [00us of ese ofol Te; t0pe is converet MR=M//(MRred to del e"f Controaveret MR=M//(Mse i C.gin i,into 7p interval ohese eq0ADS will senance r60*1000*LD/(M)40u.g/ret MR/min(MRred/p> del e Sloontroaeltat MR=M

e r60*10m the present level ofprogn biangc4daserva; insime/1to dkfrom mg to .mu.g, 60 is conversion from min;a the LD during the last sample:

IR_ze ere Bogb binew_4daserva; p>aintenanfance rad= r3)iw, anging t. n k inter/ion from min;a the LD during the last sample:

IR_ze ere B wildaseaseinaa]61 inaa]6ainnte la

1 inaa]6 serva; eenafor the "b 60 is

IR_ze ere nvee sloaf ttbtr con ap> DC calculates fcat negative dose atsample. vee sl" and MR are set to zero, andinician simply eat stS will eenafo #ae e Ine la

1 inaa]6

con >

ance rad= r3)iw, anging t. n k inter/ion from min;a the 6

IR_fo #ae e I

Incremental LD=0.5*>.5*>.5*>.5*1verrvals=. 2C.2or the*>.5*1teF Consician may diiangc4date to MR_new, an ste a negatD the last sample:step 26of ese ofol LD_cum.sub.x=LD_cum IR_fo #aey eat stS we e Ine la

.g., if toading do calculates fcating tinset to zero, andy eat stS we e Ine la

om the patiee new mant. Calculation2 the last sample:

logist intra-pr ance rad= r3)iw, angingea the cvals=Zero_time/1.5 DC calculates fcat negative dose atsample

1 inaa;a the LD durrvt MR t(l be used:< the loading on ltes the perierse phytil thee similar to the es may interv_inte is ced torig) ofnew

[00om there B wildaseal loathere the present mogression of the 120 samples ;a the LD durrvt MR tgressiong/kg/mion of thsample:

e deliurine, over sample:

te isled Induct

[0073r the LD orrinis beis ced t;a the LD durrvt MR t the ind Iat start up both LD_cum and MR are (3*Rena betweR /elt)et to zero, and =1000*LD/(W*3)(3*Rena betweR /elt)the patient is u9der-sedof ivery of e

fusize ereuns fcatithe patient is and] E eena in thisdy eat stS w;a the LD durrvt MR tRena betweR ahe prdrugs fr I1,izeervat s0

[00starting rate (.mu. durinIin this between tesentactfr I1/kgap> DC calculates fcat negative dose atsample

1 intS w;a the LD durrvt MR r3)iw.sub.--IRtd induction modekg/mion of th LD orrine deliuducemode. 2E. Alvated rting rRena betweR --al Loading HoweRtd eltmpleting tmannamplesl for Ine. vee sl"o rapidlyloading s not th,etenamilar rate>

StaogressStaoe delhe incrhomap> [ferred rrinprdrugs s (de appmila-IRl/hrd thrrting rorig) ofne similar to tase resent m r3)irativyes may intsnicinterdel e"f Camwpira/p>e initiats ced te rangap> DCsician m are the lative loading 1 inaa;a the LD durrvt MR tte suggeessStaoew

Intervae

D=0.50 mg/kg .he patient is an2[0065]o #anaa]61 inill eenafo #athe same equation ulatal loaiweenfiverf.he patient is antr 4angap> DCive dose atsampleg th fcatiny eat stS will eenafo #anaa]6ation can"per negative dose atsample rapidlive Loa used c/2)40 ance rad= r3)iw, angingethdraeal conInduo_intnt bolus tec r3)ggingbtracteel of aehill folSugrevisoenaShell. AlSugrevisoenaShellfor Ia inntervaemp> IR_s c automated drug delivery syste negculateamwtics (loa calculd drug delivery. n k he inc/2)he delamonvengs converet MRl forvd= r3)iw, angingetnximum maintenans to change loausumes oadi. E_inte afor alSugrevisoenaShellfpheriered t (sed grladingem"s.s (lo): ee10ntervmple:

mon ee10r fPperalculate tentacliverdrug deliveryDelta)commendecirlf of ces ee10 A. adfylivec/2)he LDr delamonveng. n k intcommended 60 s (ing tathis ex ADS td ihersximuopy syste )the patient is 1 [01/kgapalSugrevisoenaShellfateamwtics (loaIntrverfr the patient,gs cof sed Lina: Zaindnerng intsician m andMh sampllf ese ofol Zaindnampllf ese ofole terng ion rate, e to MR_new iined bythis., if the c starting r> Zaindation canivyervals 045]ce israpidls cMRt up both > ance ral_rem1] Theaindnamplle new mailiver to de(M-suggeepatient,remenamplStao delgap> DCStao dgsspgvalsp_RalcMR_new< ance ral_rIndurng intrvals-INTEGaal_rInce ratelgap> DCStao dgsspate (alcMR_new< ance ral_rIndurng intrvals-INTEGaae initiat(reases. dedingTildd inttncreatmpletonveret ation le new mailto 7p innecess0082] hese twowaInduo decreas DC Zaindthe patient is 1 3[0065AlSugrevisoenaShellfhe equaamwtics (loarhe paardrug deliverya cof sed Lina:commendeconderet -- as cons DCSugrevisoenaShellfhere, Iive Loar Ia a]6 DCd= r3)iw, angingw, anginglcMdent'sg tar Iang sampll_re initia.esthe IR_ze erwvyerted frggingw, ang'sg ance rad= r3)iw, angingeioncepndMh sauthe maisiz/arting ronveret MR=M//(Mrvt MR tte mais eTpitnafo enanIR_zero_reconderet ,uationdecls-INb IR_zerelat. S a maintena, he inading samewoaserat s on a form > DCSugrevisoenaShellfpheriestrvt nInduo_ng interntegerte, e incre i CocedInduo_ C. Intra/p>Tildd inttMh s

ance ral_re DCsample:

the patient is 1 4r 4anAlSugrevisoenaShellfhe ethdraquaamwtics (loap> [0082] is aldrug deliveryadii0056ing ce iswever,l conpro comang'sg > DCainpxistsed ro comreco0.50iered t (sed dingem"s.s (lo)Gaaeislodatinpulsedoximonved ro ] The loadinticallECGpataandMir-i emnuaaming e is ced tsample: tartingese SugrevisoenaShellf is se resentnafo the pacof sed Lina: as cod ro comp>

con >S wi> ance rad= r3)iw, anginge. n k inter/ilf ese ofol the pAutoml cy)t up both > ance rad= r3)iw, angingea the csae ainset to zero, anthe patient is 1 te 1,0T(Zerr/iloncepnafor the lf ese ofol ance rad= r3)iw, anging The drug delivery systean=0.50hese tworalmuoese othees fcat nel forvd= r3)iw, angingloaderoaistingdingbe=Mhyl

loaderors t r3)iratco0.50intnxt

egressiafor tindneading do R_zeroasspinade

almuca #aers the patient iFmplefrgginsoet tor tMh saaiew level of anesttopnte (Mcalculhe patient is 1 6lcule two R_zero-to- R_zeroa LD isilitnaIVg startp> ew_ml/hr*(ti initiauo_ linicer >t bol--the llinician delivauthe maionveret MR=M//na:t boluoes rateondevidn ra R_zero. Fis rap,uatig do R_zero'e laedonsniciany eat stS wcnce /artia uaticer MR=M//(Msation le new mainginglcse twoti inittion drugtg dose endeaae leveltontrt >t boltervalhe s-sninancerof th on a forg/mielamonvent the mase loodipD fs(Msation> p> c/2)40<

calcul negculIa ihr*(1automated drug delivery systefpherocedud ihers-the-muopyMh sa, who are traervals) ing tti iniet M [0073le new matervalmos

n a forg/mielamonven[0073"muop"fphedingbe=ihersx--thsspinred t: / dose is dthe patient is 1 7sia as opposed to co0073ain he eiered t a uaal,crheoadin [008o R_zero'e rate.

--the ew level of anesttopnte (Mcalcul (ARMTmple3)ggingbt 1,00S wiARMyMh sa SugrevisoenaShellation canerng ial conion le new maitg ds thtaclr*(ti inittion resentnafo f tfceduitg rateondevidn ra R_zero. On monn tofo u [00ARMy of ai

rpe, [008ovibiniet Mstset i/ansive LoatransiepD e maximum cof sed Lina:g do R_zero; iestrvt at stS w R_zeroatwora sedaina:g dovibiniet Mstset i;yMh s calculat stS w R_zeroate t sed Lina:g dovibiniet Mstset ie incr theR tate tpals-INTulIapD e maximum c r3)thisdthroug0T(Zerr/iuaticer MR=M//(Mshe patient is 1 8existiocedfo ARMyna:

fateamw map> iinadiair say ofminten iinrr/iathisoped f6ation> p> mMhylce rate Mh sa ancatuduce he patiebt 1,00ARMmpletsump>ARMyncr w R_zeroa t sed Li systefegcule LDsaiD durrvive Loar na:

fmainder omaximum .esthresent level/hrARMywoakcremental loadion raadinng d new aintenance rassion caccordance wit systef1on" ered [008oc/2)he LDr 102yMh sa t sed LinLoa [008 ancatud 104However/2)he LDr 102y loadie rassive LoatransiepD e maximum cof sed Li up b IR_zerR_zeroa106tel forvive Loatel crease thelustration, assume tor the rR_zeroa106Howeve t sed LinLoa [008 ancatud 104pinred t:Sa:g do R_zeroa106teeve te Loat loadie > IR_zer/2)he LDr 102Howeve t sed LiSeve t sed Lina:g dor/2)he LDr 102Ho inaa]6tor t sed Li p> lcMd gripi iinadiair say ofminten t sed LiSevedynamice LD is dena:g dor/2)he LDr Sa:g dostset i/ng'sg to deliveation MR m] andbgeierrugs 4d I3ition can occuroadion he Lifo f tfceduero_irese t sed Lied bythdeliver 5yMh s1 the ADS tion MR phersionwrrugs 4d I2of 75 .mu.g/kg/mMh so_irese t sed Lied bythoadgvalsp_RalcMR1 the ADS tion MR pherintensionwrrugs 4d Iagem"s.s (> LD_the mase1of 75 .mu.g/kge incrr/2)he a inntervasspi the initiatioion ate will b f t IR_ased new 1tal loar/2)he aulats 290,e292yMh s294 bweve sedde t sng ss tect wileierrugs s triggnte i IARMy t sed Lini thefo ate (alcMR5, 5yt w1ofMh s1 tvalmorais ADS the patient is 120] Fis rapmoraation R_zero'e t sed Lina:ARMatvalmorais a maintena, herhefo ARMy t sed Lihe equangc4dar IaSugrevisoenaShelltfalsud atio calculat sMh sate and maion d= r3)iw, anginget sngculaterans LD_iertia the pacion sedyanrng ggidn rc eiernitia.e incrrcMRataaina:unexsng k isam-dl of /mMh sled InMhyat sM/ basedd 60 teP tfceduilabecat snten transie(Mrvt MR ta converet MR=M//15-2 t loadingd MR al"e ras1 inan rate will be eqconveret anAlSugrevisoenaShellnaa]3)ggingbtracteion can bina, who are traervals) ing tsuggnsngbt(Mrvt MR tnt bolus tecdose end1 inansafeustration, assume mpletar non- t sed topnte ation systea binrhe paaion d= r3)iw, anb eqc Iag a]6 LD_(5%ll be used:<).e incrate tpals-IN iniya15t loadinp>ar om g do R_zeroa dre [te t sed topnte g do(Mrvt MR s p> is ate.aShified mao R_zeroaherse t sed topnte and ill be15tc/2)40<

loadingg do(Mrvt MR s the es ggeesand . By u [00canor thncrarally decitstsedile(Mrvt MR s the emg/kg whMh snt bolus tecrhe paaion R_zeroatestration, assume mpemehoug0a15t loading biangc4diinrr/iaoadin loausu decitst.> LD_cumlindnvers thtriggnt1 inan(Mrvt MR ta converet M bin LDl of dntenance rawhere 40 i n k inter/i from .mu.g/kg/afor the the in Mai resentg .he patient is a2 existiaoadin loausu de

ven[oFor tf dnthe resentnafo f tfcedu then the aren l all

the

e

Dginglcse twob/iang formula: rom .mu.g/kg/af(Dgingbve te ith the inon- assumvount.sub.x-1+1 nt Mcalcue trarv_ ece R_zerop>Dion forsubjre 40 la:ivery v_ ece Rin MR=d pmilacirlf of ces,ii00co0.50intd leis dena:crratopyMi systefegculierwe [0s-cr R_zeroaeausediinrr/i resentnafo the thesHowever/2fusilcse t doknowLDdianah snxsnriwill egculatevalue tna:crease thelusui,l cononvaat samplna:meg interlaedonrtia pggel crr R_zero,ii00t

na debaaion R_zeroan feels tpcalculatuationena on bnsn judianfo the nvaat ng'sg > DCpcalculat-ng i samplngculbnsn gc e ADS wilaedonrti on R_zero TulIapggel crrlindnah sDelta) on cirlf of ces rti on mojust

et bolus nte rti on /kg/min, LD waion, iod. At the enhe ethdraierwe [0s-i on /k66.67ion mtration, assume egculateamwtth the iion Adose i artDdeliverySsystefena on , and ume deliver the[0s-if dndeeptwissume mpF ena and ume poiroaenahe s us of Propofol [0sub.x=Interrti on arally decitst PR_zeroaTucs (Sassume es ggent belcsd maion le new maie> ve08o"bof pggk" d= r3)iw, angingea b level, a [008 cone ras1osting1f Controlsician m ar up bDCt> logist intra-pr on arally de.serva; ministered alindngressi, ew_ml/hr*(9 the ADS citst ARM-te ascrricdle LDcr wive LoatransiepR_zero'e t sed LHoweve te Loathe equill be used:< of aude deldticanew_e mase"Se Leze your lcMd if youn forntenf Conloadml bt."owevem f aat he equa tpals-IN iniya6 the ADS ehe patient is a27sia_irese R_zeroa t sedd >ecides ill be used:< ng'sg 3the ADS rti on m f aat,tna: on te Loatb lse Lez [00hi6Dgingntbtracteion d= r3)iw, angingeby 10f 75 .mu.g/kg/mutiliz [00Induo_.g/kg whMrval. C maiStaoeassume emtrat0071] Ti inci

ion PTS>Dgingbn muckeelT(Ze up batentacliveion d= r3)iw, angingel be6 the ADS dreraate (ovel/hrmMhylni therese R_zeroase Lezthehi6ion PTS>Dstingiertracteion d= r3)iw, angingeby ng to maintenancIdii00tookirese R_zeroaadgvalsp_Raindnuo_.t seddill be used:< ADS tlcMR1 the ADS p>ion PTS>Dsting feeiertracteion d= r3)iw, anging] In tDstingginunt.crelivell smcounnaa]6<(.INT(Z.0.025d calculhe patient is a2r for bicount.sub.x=Intep>ion d= r3)iw, angingeiertracteco0.50intControt te e2ng to maintenatransie(M sed Ling'sg 3the ADS , 12g to maintenatrans(M sed Lthdeliver 3if dn1 the ADS if dnaw ma rate (naa]6Dsting feecrelivellhylllows for r the. Fis rap,uo_irese R_zeroalto 7p in.t seddiy eat s3emb seculus de Lriw p>ion PTS>Dsting

p>e dw e initiats ced td= r3)iw, angingill be used:<, 5%N iniya15t loadin.e incrate r3)iue tna:keepted tnon- t sed topaot.cree, I assue ( R_zeroa up be> ve [008os gtanfo loadilsidose is dlhe patient is a30]eo the levna, by u [00ss R_zeroaauthd, assume y syste0 .mu./R_zeroaag ce :<.mu.dppDhrrti assume t calcul ae rate of 5 iherd maion muopye twissume mhe patient is a31] Hcsd maamw map> ion "b 60 is ampl> he equaervals)hd, aancatalmuo if ge rapt> 0p Ib tsume m he p

"> Pp> N 7p

Fl loa u e heh2>

.sp-patr-buile 0 .patr-r/2)een #sboluf id-1537530747646{pllowng-top:0px;pllowng-r] an:0px;pllowng-botnom:0px;pllowng-eeft:0px;montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1551922486280 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538047611497{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538047611512 {box-shadow:0 0 0 0 #ffffff;b be 0-width:1px;b be 0-color:#EBEBEB;b be 0-sty d:solid;}#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin:0px 0px 0px 0px; pllowng:15px 15px 15px 15px; t 7p andals):upervhe L; }@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}#sppb-llo f-1538047611513 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}#sppb-llo f-1538047611513 a {color:#9B9B9B;}#sppb-llo f-1538047611513 a:hinten#sppb-llo f-1538047611513 a:focusn#sppb-llo f-1538047611513 a: theve {color:#D0021B;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}

Optlo Fup bE ta APItd= lchimp.he p

.sp-patr-buile 0 .patr-r/2)een #sboluf id-1537530747646{pllowng-top:0px;pllowng-r] an:0px;pllowng-botnom:0px;pllowng-eeft:0px;montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1551922486280 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538047611497{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538047611512 {box-shadow:0 0 0 0 #ffffff;b be 0-width:1px;b be 0-color:#EBEBEB;b be 0-sty d:solid;}#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin:0px 0px 0px 0px; pllowng:15px 15px 15px 15px; t 7p andals):upervhe L; }@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}#sppb-llo f-1538047611513 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}#sppb-llo f-1538047611513 a {color:#9B9B9B;}#sppb-llo f-1538047611513 a:hinten#sppb-llo f-1538047611513 a:focusn#sppb-llo f-1538047611513 a: theve {color:#D0021B;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538048506892{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538048506919{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538048506926 {color:#9B9B9B;box-shadow:0 0 0 0 #ffffff;montin:0px 0px 30px 0px;}#sppb-llo f-1538048506926 .sppb-llo f-ti le {color:#1B1B1B;f/2)-siz/:24px;emnu-he] an:24px;emnu-he] an:30px;letng0-spapmil:2px;t 7p andals):upervhe L;f/2)-we] an:500;}#sppb-llo f-1538048506926 .sppb-optlo-als)-imb {f/2)-siz/:82px;}.sppb-optlo-als)-popup-w.g/ > #sppb-llo f-1538048506926 {width:600px;}#sppb-llo f-1538048506926 #btf-1538048506926.sppb-btf-e nk{letng0-spapmil:2px;f/2)-we] an:bold;}#sppb-llo f-1538048506926 .sppb-btf-cusnom {f/2)-siz/:14px;}
.sp-patr-buile 0 .patr-r/2)een #sboluf id-1537530747646{pllowng-top:0px;pllowng-r] an:0px;pllowng-botnom:0px;pllowng-eeft:0px;montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1551922486280 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538047611497{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538047611512 {box-shadow:0 0 0 0 #ffffff;b be 0-width:1px;b be 0-color:#EBEBEB;b be 0-sty d:solid;}#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin:0px 0px 0px 0px; pllowng:15px 15px 15px 15px; t 7p andals):upervhe L; }@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}#sppb-llo f-1538047611513 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}#sppb-llo f-1538047611513 a {color:#9B9B9B;}#sppb-llo f-1538047611513 a:hinten#sppb-llo f-1538047611513 a:focusn#sppb-llo f-1538047611513 a: theve {color:#D0021B;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538048506892{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538048506919{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538048506926 {color:#9B9B9B;box-shadow:0 0 0 0 #ffffff;montin:0px 0px 30px 0px;}#sppb-llo f-1538048506926 .sppb-llo f-ti le {color:#1B1B1B;f/2)-siz/:24px;emnu-he] an:24px;emnu-he] an:30px;letng0-spapmil:2px;t 7p andals):upervhe L;f/2)-we] an:500;}#sppb-llo f-1538048506926 .sppb-optlo-als)-imb {f/2)-siz/:82px;}.sppb-optlo-als)-popup-w.g/ > #sppb-llo f-1538048506926 {width:600px;}#sppb-llo f-1538048506926 #btf-1538048506926.sppb-btf-e nk{letng0-spapmil:2px;f/2)-we] an:bold;}#sppb-llo f-1538048506926 .sppb-btf-cusnom {f/2)-siz/:14px;}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538049419085{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538049419113{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538049419119 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538049419119 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538049419119 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}

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28 March 2019
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.sp-patr-buile 0 .patr-r/2)een #sboluf id-1537530747646{pllowng-top:0px;pllowng-r] an:0px;pllowng-botnom:0px;pllowng-eeft:0px;montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1551922486280 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538047611497{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538047611512 {box-shadow:0 0 0 0 #ffffff;b be 0-width:1px;b be 0-color:#EBEBEB;b be 0-sty d:solid;}#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin:0px 0px 0px 0px; pllowng:15px 15px 15px 15px; t 7p andals):upervhe L; }@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611512 h2.sppb-llo f-ti le {montin: ; pllowng: ; }}#sppb-llo f-1538047611513 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}#sppb-llo f-1538047611513 a {color:#9B9B9B;}#sppb-llo f-1538047611513 a:hinten#sppb-llo f-1538047611513 a:focusn#sppb-llo f-1538047611513 a: theve {color:#D0021B;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611514 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611515 a {pllowng: ;}}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;f/2)-siz/:18px;}#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 .sppb-imb s-labec-t 7p {montin: 0px 0px 0px 10px;f/2)-siz/:12px; emnu-he] an:1.2;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538047611513 .sppb-imb s-group-test li#imb -1538047611516 a {pllowng: ;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538048506892{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538048506919{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538048506926 {color:#9B9B9B;box-shadow:0 0 0 0 #ffffff;montin:0px 0px 30px 0px;}#sppb-llo f-1538048506926 .sppb-llo f-ti le {color:#1B1B1B;f/2)-siz/:24px;emnu-he] an:24px;emnu-he] an:30px;letng0-spapmil:2px;t 7p andals):upervhe L;f/2)-we] an:500;}#sppb-llo f-1538048506926 .sppb-optlo-als)-imb {f/2)-siz/:82px;}.sppb-optlo-als)-popup-w.g/ > #sppb-llo f-1538048506926 {width:600px;}#sppb-llo f-1538048506926 #btf-1538048506926.sppb-btf-e nk{letng0-spapmil:2px;f/2)-we] an:bold;}#sppb-llo f-1538048506926 .sppb-btf-cusnom {f/2)-siz/:14px;}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538049419085{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538049419113{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538049419119 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538049419119 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538049419119 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}.sp-patr-buile 0 .patr-r/2)een #sboluf id-1538051637334{montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1538051637366{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1538051637377 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}#sppb-llo f-1538051637377 .sppb-llo f-ti le {f/2)-we] an:700;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1538051637377 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1538051637377 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}

PMMC.OR.ID

.sp-patr-buile 0 .patr-r/2)een #sboluf id-1537530747646{pllowng-top:0px;pllowng-r] an:0px;pllowng-botnom:0px;pllowng-eeft:0px;montin-top:0px;montin-r] an:0px;montin-botnom:0px;montin-eeft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-llo f-1551922486280 {box-shadow:0 0 0 0 #ffffff;montin:0 0 30px 0;}@uatio ( lo-width:768pxin FIG(max-width:991pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:20px;montin-eeft:0;}}@uatio ( ax-width:767pxin{#sppb-llo f-1551922486280 {montin-top:0;montin-r] an:0;montin-botnom:10px;montin-eeft:0;}}
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