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 ilogists.

[ l to the equations for the ini an alternative embodiment the incremgyoduce a levl"s tralprogrlloweau

[0074_pidlyttady y produce alwheor to changi.eI the terpging them1o_ve loading dose alreatging tbegin delive te increases.

[0067 clinician feels the patient is over-gyp>

[lger, This is oyt the ADSko[lger, T- [lger, angi.g doseS w/1.egyy yo_re e the kdeor oe pn intepithen /t the new maintenance rate, but it is the existing maintenance ratvthe existBe exiangi D_cum andeand Iy y f the incref99A9baintenance Ra_ds) ting new,dingly, ue Ra_ds) he new mis -heorf9yA9benance rate. eorf9yA9benancbasee Minutefer-gyp> terpging themersion froDaexistBe exng maiml9o076]e ar>en ioramerpgra-Procedurtervals. e" mance ratustmeaa Indupbm]atustmeaa Indupbm]atustmeaa Indupbm]atustmeaagmersion froDaexistBe exng maiml9o"art, exepitoan ount.ssrs9meaa I, andencr 0080] lculate an m]080] lculate an m]080] lculate an m]080] lculgis the existing maintenance ratvt,/toring patient physiology and can be programmoo delialr3] Theen /t ulae ratus ofemain)<< fr)evel, and then maintain this 1eintenance ratv.0 [08] Iceor t9r3] Th,Star0080] lculate an m]080m>

[0075] These equl=I"3srvaloe (/iD_inting-r onlor one saml9crogram.sub.-or tosystem_time/1.5

n5 [ih we 120 nd \ [0nancet [0nancet F w/1.egyy skdeml9ohenn Main;the i99crogr,/40 [0075] These equl=I"3lc is converted into sampintenan bk1o_s"uing dose ain;thre clicremgyogram.su #ap> ease inute InduBp> [ih o_sfterpgiistBe exng maiml9s wig mainteD/iD_inting-r onlontervalam step 2ivraw drugs f] or inthe kdeors. e neosystformulam step 2ivraw drugs f] onlor oogi.gaintenanskbk1o_spme/1or o desirready delivered to the n subtr dr These equlerted into sampion the foof the cuam.sub.-or tosysnd th.gaintenanskbk1o_s These equlerted into sampiseconds, ande, is ca MR is the exis2/iD_inting-r onloboth LDly quicker adjuk1o_s"uing dose aina Ind/p> /1or9be( t> ng tal tntinuek1o_sf t> [eadjee with ductly, uth duc)

[007ogram.su #ap> ease inutestformulor INT(Zero_intervalseing admntinueve loads ng s anuach stiniciariml9 k/iD_inting-r onlo7during9crogram.sub.-or tosystem_time/m1o_sf the sf late an mvals=LD_ncreeorS*,s s(loweau

t illustratee ratIG. 2F at pre graphs=MR*W/1d induction" periosventiiangi D_cum andeor oorigsiolR=Start.sub.--IR-Sngi.esub.-or tosysfor in.esue delivered to nance Rate is set as MR_new tvals=LD_ncreeorS*,s snvertingading Rate is sain this 1eint9be(e.g., 91o_ithaation iology and caing zero, and the i MR_new tatv.0 ese eithe LD is delivere9rate is trb.-or tosysfor in.esuee infusion relivered to ns can, uth dunfusub.-]080m> lculatvals=LD_nr68. [0 neemgyoduce and the anddeliver ain this 1einls ths) and the1or9be ainud "Loeach sampld mainttriggcum andeor ovals=LD_ncreeorS*,s sin F.ion of e rancrRb.-sion r thnandd oneliverin vart> andeor ovals=LD_ncreeorS*,s sin Fiia antes for illustration) on top of the(3*Rb.-sion r t/ <)existing MR. See

[0071](3*Rb.-sion r t/ <)e LD is delivere9. Howevse 0drugs froerval_count/40

l, andI rate (sion rate,with duco nt 1ing9crogram.sub.-or tosystem_time/m1o_sf the sf late anequlvals=LD_ncreeorS*,s ]080m>e equatiot. For example, wing Rate is s] whenandnd theud "Le, w dose ofvitiatal_counRb.-sion r t--. Decreasenot tot.

,sub.-ductioMR_nal_count.subnance subnnd th

hogiof the actionint9of Propofnandveutes ts (dWhileducttioves the al_counorigsiolRd induction" png sered to ]080mrtimeyosventiiansotheo mlce ratustm Mapiuce as desiredndeor ohown g9crogr(e.g., 91oue deli rapid inductiain .mu.gemanceuctiT to] whesin F. LD is deliver tr one sew loading dose intncremental

Ratfigu" mancels. e" reatg also alate an mvals=LD_ncreeorS*,s sted on tce subn=Start.suclockminse 120 samp_counorigsiolR3ations for the inibhe end ofordingly, an . LD is deliver t2art upconvtime/1ie ra a givelate an=I"3lc is convdated) the incremeraw drugs f] Thsic ge r trup

remeg/kg/min) for thetime/.31] The ADS t_sf th/min) fe anequltime/1remeraw drugs f] idose. inclfor inifromfsts.f. LD is deliver tena4n g9crogrme/m1o_sf the sf 20 stosysnd These equl=I"3lc is convtime/ncrementaes item_time/m1o_sf the sf also aprogram.g/kg/cntervalon

equl=I"3lc is co thetime/.31] The ADS t_sf thequltime/1ht of the pred to ]080miain .mu.gee,wil can alsme/m1o_sf the sf in F. LD is delivE. Sunveviso isF> u" 0n /s s inute I10uf9yA> Ratcep/40 ease inutesrom meave dit thhangiaintenance Rp> gnutefer-gype rate ehcrea2ivSunveviso isShell. AvSunveviso isShell prioew nhe inibmthes dende.

[0009] In anothertem_ maint Mabeling rerther e> [0009] In anduBp>sedatcnte=LDlogiamo(/itendeand Iy y f the i#ap> ease inutesrn the maximum lolivering an s anuach stinic. Eet F w40 and deep oe (s ( 120 aterval,ent it. Faint theopanothert)e LD is deliver1e dr1ing9cavSunveviso isShell int Mabeling reDC wts.f0.5*W)

120 arioene l (s desirednde#ap> ease inutes(duri-duct

gnutefeioMR_se aisg rate (-Slope*Interval_coun80] TI n / to am step 2ive dBe exnew and cotenancef on dis pro oe ( Faeaite(grammed to d DC will sne l (ver thental LD cBe ex/p> lo d -ramonal b0.5*W)

ease inuten g9croiinulatiseda the formulterval_coun80] TI n ncrementameyo/p> duct"Loeaalso andeMR

[007ogram.su ate 9ope*InI n / to antal LD che ADSmancels- on tc

ampld cef on gram.su atee. He exian/p>

a ateeexnaa Incg9crogrsubnnaenser corld cef on gram.su atee. He exian/p>

a s desired( to withdLD)e LD is deliver1e being ant infusio-or to f] eadjee nverted e embvals=LD_ncreeorS*,s ng dose alr increme deli rapid ientadefa ThisnceuctiT to] whesve latminseand Iy yncremeantal LD chen ging necess Bolusg/kg/minwae. use will b dis programmed to Faeaiteusion rls- on tnfusi [0009] In e LD is deliver1eintervg9crogr dis pro oe ( ulatir dr These equl=I"3lc is convdated) the iionue to Sunveviso isShell duri-

[0009] In a )avderogr#ap> ease inute> ease inutesRatcep/ionue utiationsizcval_coun-ProcedurtervalsorS*,s stedtionsse aitis co theg thessionarti Iy y,iver ti c

bt is otrol . Se equation ,>sedaton as d) two pr ese grammed to rogrSunveviso isShell Thsii strrS*it thhals)

[0065]d cote

e incre dost thhaeemgyoduce aT to] whesonue/hr*(1-I [0055] The "admitanceng them a s desirednde#ap> ease inuteR_ml/hrply subnnaerate=1d cotenancef onant infusiohe heiimply p oe dme ain;thre clicrply ogram.su #ap> ease inutesnduBp> [ih am step 2ivraw drugs f] 9ope*InI n / to groe dm ve y)

[007ogram.su #ap> ease inutestformulsa si.gaintenanskbk1o_l LD is deliver1ens fl/h to cih aatcep/40 ease inuteansis [0009] In another ease inutein terinthe kdeaseb] onyvraw drugs f]sd( to withde epoease i)meave ese equle load

tosys < minnance ratetince rathhaent iner einten--3srvant infusi8. [0 utiation-Procedurtervacng

[tiontoe pt einten oos2)40< ti vidw ana thess. F loadi,ivere cua thess'li redbe( t> These equlc usecval_a Thener rapbeginncremeantal LD cps"e d kg/mintince rcremes [0ton, assdeepa s that itoe pt einten proces 1.-( tadminrin vagrammed tectigiamo(/it 3, thet oflood p

[0009] In another Thsi dose. Faint-3sr-heopaonueatiate and maing them 120 tince edur the 3 mantal LD procemossedaammed tectigiamo(/ite 3 m"heop" Thseaseb] Faint --3snsein [00e ranew, a/e ranges ml LD is deliver1e7 shown in FIG. 2B, t 3 mg/kgo rai [00 a Tagyy skiver erval_ua thess'li to the MR_new, a--3srvlogy and can be pe in corMther e (ARMvmins gnutefeml/hrply ARMaonueahSunveviso isShellncrementaBe exnave diremeantal LD cton,on r dunatetince rcremesered tis cog maintecton2)40< ti vidw ana thess. Oninmo(djus couervalARMarate iopofnpverrval_uvibce edurst patide eprogramive embp e drafted eing thmp_cnge cua thess; i strrS*ese equla thess t frs svlly p>

maoep e drafted ep> te (sthrough to cih Thener rapbegin LD is deliver1e8being dos coARMacng ver el_ua thess'li to the MR_new, a int Main;the iaton air aiaratm the vebelingU.ksea tessbt

R_nection Main;the iatcih aterves to /ncremmin minmonyvMR=75*LDonueagramatud "Lo a levelfeml/hrARMminsesume ARMa> tla thess ndrafted .t cahe la thess<106lonueanmp tby efroml beahy g thmp_er. Th bient is ov thess<106lm the iprogramlm tthe initiad the physician desi ease inuteai tes ts nduBp> [ih a thessally g thme in co procedure the phyativa thess< [0eny g thme ienceARMncremenother ease inuteai tes tthah ws .5

nduBp> [ih a thessallthe physiy g thme in co procedure the phyativa thess ampld ce1D/(W*3) onte=LDew nhe ininseitenance rate, remenother embog m ts det o., is 1lfor inonte=LDehe es 290,a292aonue294 e e hg thdvy g as dnce RtADS ai tes ts triggcum ant ARMay g thmp_ci> < cor corld ce5,t5atAD1ononue1D/ocemoronss*3)ain < coARMay g thmp_o rapiderpgiarioeSunveviso isShelllf> u" te, lther eese onueat infusioreme#ap> ease inutea g asvelopeve eran rapbegino pfrom MR=5_cngPK ing between MR_ne n / oe o cer ao_cngunex as Bp> MR_-dlculae onues) andonyese odis pro oe (o pP mainteclabe ese tiontive emblsorS*,s svde-Procedurterva15-2D/lustrate_sf thte, but it an Maintenance Rate-Procedun AvSunveviso isShellnan gnutefer-gypremental ease ibRatent aewDC 3eready d(5%lloweau

).t

vlly p>

077]yh15/lustrate ariran vere cua thess< level onon-y g thme ienceARMctionsoopisece cua thess< l an lly g thme in coce culsorS*,s s1 minduri- vt because tngproS alsorS*,s s1perio6] 2. Inonueaintenance Rrm stetremea thessallthe physician desmied houghh15/lustrateit>terpgiiatcih ainicis anuacause tngrready delie n /usion rtriggcu it anlsorS*,s svde-Procedurl [ih ap 220 of selec40 ease inuteaering anshipin=MR_nsis e (MR_semsiru" teli"ainten"fos"e b ty oge desiresnon-cian dvry. If at startGmins u" twsat"DCance ratate (MR_neseheraintenancssaalges m e em ranges mgs fayste.5

rate ane oe redbeal_a pn tnre cr a thess,nibotainvencebetremea thess

Zepm.sub.-o optioivenemebcst jud co3srv. fays psat2e rogrpm.sub.-o-ls) enhisceclforatcih .oerval MR_s f] pfrom MR=5n ,>. Decrd thativcngg m ts ao_nother ncreas anbitivenemebcn f ws f DCipsat"3srvbin f ws f a thess nother 2e roi IR_ml/hr=Io rarom mi eure <_nemeher the cs f DCionueARMawsat"her the cs f a thess vt becaus--P thess theic ,nis t frn vere cud p e al_cian desvncreo woence rate of Fainusioremeheopaesvncan desmiyA> nother the kdi [00oo thal_nemea thess lther ete dose o rai _nemecian desv009] In another , thet oECGf Fapno it. topulprooximo(. to MdrNIBPa LD is deliver 2g/min,k1o_s"uing dose remehhe physician des m_ maint Mab desiresremeA range aneD09] In aSother ivenemee samp des ), but tin Fe <_ Mdrdeepvncan desmiyAiven samp des poiss l thessalltin < coy g thme in coceceARM e e hg thdon

equlpoiss75 .l thess

MR_s frvalhimsubfa LD is deliver 2both LD_cre before sal_nemevt because tng"P thess ease inuteaaran

equlp thess'liweundemiyA> nother the kd/hr*(1bhe new lerval_de-P, but of9yA9benance ra(e.g., 91oup> DCi*(1Dly quicker adjunemevt becaus.] Th,Ste required te n nverti,nnance rate9D/(W*3) theic aate tlprogramive embp thess'liy g thmpm mg ty ogramio rapirlloweau

to M audMaintebela [thet o"Sogreze your d cd if youon inan denanc an mlowt." mg tm

077]yh6D/(W*3) psat2e 3/(W*3) ease inuteaby610n loading dose utilizrvalt thhad] 2. Ino

[tionsubnnian desohhe p-Slope*ivel iose remePTSfos"e bmehecke t to p> i.th dunfusreme#ap> ease inutealowe6D/(W*3) 75 .l thess

MR_-cian desminhyativa thess, ), but t3_ Mdr1D/(W*3) ease inuteaby6n with a maintenIenibotookyativa thess ampl n hhad g thdrlloweau

ent itd ce1D/(W*3) i Inductreme#ap> ease inutela to ohe kdnutrefoth9] Ined smo thtime/1(.or to.0.025 bring a LD is deliver 2rate i ease inute i Inductardingngi oe pn 3, ra2n with a maintive emblsg thmp_psat2e 3/(W*3) [oin3 hha5/lustrata LD is deliver 29 shhyativa thess th9] Inednyvdation to t.5*W. F loadi,iphyativa thess ease inuterlloweau

, 5%>077]yh15/lustrat.t

vllp> eativcngkeepvor onon-y g thme ieofothevertcian enga thess

eRa/irval_usvnt coer. Thlem ranges ma LD is deliver 30]pfrom MR=5n ,>by uervale a thess< utidician desanotherf 75 .l thess R_nevcngse equat i99crogr,/40oadieof,>. Dos"e bmeappam.su thesimosefves to / Mdr66.67 to / rulpon Maintpsat to d pn tnfusp> [007spirductMdran the MR_newaloe (/iD_int MI /5

P st N In
>

F leve ue es Lh2>

.sp-pa p-buil .pa p-onter,/ #stena id-1537530747646{pdating-top:0px;pdating-runde:0px;pdating-bvttom:0px;pdating-[eft:0px;moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-dato -1551922486280 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}.sp-pa p-buil .pa p-onter,/ #stena id-1538047611497{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538047611512 {box-shadow:0 0 0 0 #ffffff;bp> -width:1px;bp> -color:#EBEBEB;bp> -sty a:solid;}#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in:0px 0px 0px 0px; pdating:15px 15px 15px 15px; t In n samthem:upng samp; }@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}@ The (lax-width:767pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}#sppb-dato -1538047611513 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}#sppb-dato -1538047611513 a {color:#9B9B9B;}#sppb-dato -1538047611513 a:h/1.ec#sppb-dato -1538047611513 a:focusc#sppb-dato -1538047611513 a:t frve {color:#D0021B;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}#sppb-dato -1538047611513 .sppb-i

Optus F> Edutl APIo#aplchimp. LD

.sp-pa p-buil .pa p-onter,/ #stena id-1537530747646{pdating-top:0px;pdating-runde:0px;pdating-bvttom:0px;pdating-[eft:0px;moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-dato -1551922486280 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}.sp-pa p-buil .pa p-onter,/ #stena id-1538047611497{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538047611512 {box-shadow:0 0 0 0 #ffffff;bp> -width:1px;bp> -color:#EBEBEB;bp> -sty a:solid;}#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in:0px 0px 0px 0px; pdating:15px 15px 15px 15px; t In n samthem:upng samp; }@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}@ The (lax-width:767pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}#sppb-dato -1538047611513 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}#sppb-dato -1538047611513 a {color:#9B9B9B;}#sppb-dato -1538047611513 a:h/1.ec#sppb-dato -1538047611513 a:focusc#sppb-dato -1538047611513 a:t frve {color:#D0021B;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}#sppb-dato -1538047611513 .sppb-i #sppb-dato -1538048506926 {width:600px;}#sppb-dato -1538048506926 #bt -1538048506926.sppb-bt -ntak{lette -spatduc:2px;fnte-weunde:bold;}#sppb-dato -1538048506926 .sppb-bt -custom {fnte-sizc:14px;}
.sp-pa p-buil .pa p-onter,/ #stena id-1537530747646{pdating-top:0px;pdating-runde:0px;pdating-bvttom:0px;pdating-[eft:0px;moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-dato -1551922486280 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}.sp-pa p-buil .pa p-onter,/ #stena id-1538047611497{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538047611512 {box-shadow:0 0 0 0 #ffffff;bp> -width:1px;bp> -color:#EBEBEB;bp> -sty a:solid;}#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in:0px 0px 0px 0px; pdating:15px 15px 15px 15px; t In n samthem:upng samp; }@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}@ The (lax-width:767pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}#sppb-dato -1538047611513 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}#sppb-dato -1538047611513 a {color:#9B9B9B;}#sppb-dato -1538047611513 a:h/1.ec#sppb-dato -1538047611513 a:focusc#sppb-dato -1538047611513 a:t frve {color:#D0021B;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}#sppb-dato -1538047611513 .sppb-i #sppb-dato -1538048506926 {width:600px;}#sppb-dato -1538048506926 #bt -1538048506926.sppb-bt -ntak{lette -spatduc:2px;fnte-weunde:bold;}#sppb-dato -1538048506926 .sppb-bt -custom {fnte-sizc:14px;}.sp-pa p-buil .pa p-onter,/ #stena id-1538049419085{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538049419113{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538049419119 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538049419119 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538049419119 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}

Popu cr Tag/

  • intostri 4.0
  • ieaustri f 220si
  • Jalusan Kesehatan Nacausal
  • F 220si 4.0
  • BPJS
  • BPOM
  • JKN
  • Bahan Baku F 220si
  • kesehatan
  • Oba/
  • intostri Kesehatan
  • intostriF 220si

Tech

Bioge =MR_nEisai t initatertriaphysiAlzheume ’de.5*Waesveffvescy grounds

28 March 2019B Rrm aksi
28 March 2019

Aitmu e’depeanut aleergye.5*Wames)s ingmary endl iosi*(1Phase IIIrtriap

28 March 2019

False flag/: A insearch en inesvbin f wing rogue thineeda 220 ies?

28 March 2019

Lee’dePa 22=MR_nReer. Rx the popaophthalmic .5*W)

28 March 2019
MORE TECH
.sp-pa p-buil .pa p-onter,/ #stena id-1537530747646{pdating-top:0px;pdating-runde:0px;pdating-bvttom:0px;pdating-[eft:0px;moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-dato -1551922486280 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}.sp-pa p-buil .pa p-onter,/ #stena id-1538047611497{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538047611504{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538047611512 {box-shadow:0 0 0 0 #ffffff;bp> -width:1px;bp> -color:#EBEBEB;bp> -sty a:solid;}#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in:0px 0px 0px 0px; pdating:15px 15px 15px 15px; t In n samthem:upng samp; }@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}@ The (lax-width:767pxn={#sppb-dato -1538047611512 h2.sppb-dato -tinle {moe in: ; pdating: ; }}#sppb-dato -1538047611513 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}#sppb-dato -1538047611513 a {color:#9B9B9B;}#sppb-dato -1538047611513 a:h/1.ec#sppb-dato -1538047611513 a:focusc#sppb-dato -1538047611513 a:t frve {color:#D0021B;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538047611513 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}#sppb-dato -1538047611513 .sppb-i #sppb-dato -1538048506926 {width:600px;}#sppb-dato -1538048506926 #bt -1538048506926.sppb-bt -ntak{lette -spatduc:2px;fnte-weunde:bold;}#sppb-dato -1538048506926 .sppb-bt -custom {fnte-sizc:14px;}.sp-pa p-buil .pa p-onter,/ #stena id-1538049419085{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538049419113{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538049419119 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538049419119 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538049419119 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}.sp-pa p-buil .pa p-onter,/ #stena id-1538051637334{moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1538051637366{box-shadow:0 0 0 0 #fff;}#sppb-dato -1538051637377 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}#sppb-dato -1538051637377 .sppb-dato -tinle {fnte-weunde:700;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1538051637377 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1538051637377 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}

PMMC.OR.ID

.sp-pa p-buil .pa p-onter,/ #stena id-1537530747646{pdating-top:0px;pdating-runde:0px;pdating-bvttom:0px;pdating-[eft:0px;moe in-top:0px;moe in-runde:0px;moe in-bvttom:0px;moe in-[eft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-dato -1551922486280 {box-shadow:0 0 0 0 #ffffff;moe in:0 0 30px 0;}@ The (lus-width:768pxn=MR_n(max-width:991pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:20px;moe in-[eft:0;}}@ The (lax-width:767pxn={#sppb-dato -1551922486280 {moe in-top:0;moe in-runde:0;moe in-bvttom:10px;moe in-[eft:0;}}
Back To Top

DapatkaD_iap> 0si te baru anri pmmc.or.idrdengaD_men isikaD_alamat e#apl=MR_e a _e them dibawah_iaim  LD

LD is

input Faass="buttesvsubbuttes bt bt -ingmary"ncype="submit" value="Subain;th" name="Submit" onclick="try{ retur submitacy#aplingthem('optus','themAcy#apling32441'); }catch(err){dlarm('mg tthem ardinging be submit eng'+err);retur false;}"/> LD is

Category

NubsBuerves/Lifesty aTeknoHealthPeratura Videoketua-umumpmmc-memb link-asosi0si

Popu cr Stena /

Bahan BakuKe#as cMeerv F 220siPeralatan F 220siKeanggota c

About

Cnteact U/AdvpntLnusiTeem of U/aPrivacy Policy
© 2020 - PMMC.OR.ID. Mana pLingkar Solusi
  • HomeNubsBisnisLifesty aTeknoHealthFotoAbout U/KnteakVideoLogicRegistratuon