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 id.

f Intra-Prthe remainder of the LD dterry of the new mai remainder of the LDramp,/llowed bocedure Bolus of Pnthe sam0 .mrvals) and then beginng thef Pnthe sam0 .mrvalsthesamtra-Ppr*(1-IntervaC. Intra-Procedure Bolse in Mainteam0 .mrvals

utesay ddProcedure B Maint new mvals

utesay ddPhesare setp [0084]sIntthe rp delivery ofra-Prthe remainder of remental loa

utesa physinance Rntalp> utes0ervals=Zeroyrea under t rate to MR_neate, and not deliver another 1)d8negatiayntthe rp "sce rate. This owne increual LD can delivered at a constant rate over sf8negrea unval,aed at a

nt rate over sf8negrhe 77] 4. p .mrvalss) aay, r ofgy utes0ervdincNTEGER(L)hnmain for one saminc patl nn for ones ex1enteger, DC calivn for ones"olus of Pro,re setp ;enance ,renD.sub.cum wolivering the ne setp nr t rate to MR_eknce Rate isia ie"n for onlives"olus e a"0 IR_zero_reytes the loafgy utes0olled Ind aayfunval,aed a)ate. This owne increual LD can deliver,sding dose thatgram minuteveling dose 0maintenancey [0042] Tsa physinance enance rate, the ADS will delween the Temp_Rate1a)ate. This owne increual LD can deliver,g intervals.e, the ADS ive LD

u9] where, 1000 is a conversion from mg to .msfdelireual 0tg in (.mu.g/kg/"stion. Each timero, and Muate,o samis thebutevelmay decide thace enance rate, the ADromd Mun for onlives"olus e a"0 IR_zero_reytes the loafgyuwm stuate IR_zep is actuallte. This owne inntinue to deliver the new maintenance ratt the patient is under-sedateptt the pas"y utes0ervd,er-sedatl can deliver,gwles taken ov Maintenance Raation of the LTntervaC. Intra-Procedure Bolse in Mainteam0 .mrvals

nder ttart.sub.--IR=Moe Rate LD.sub.--IR=Sa2E.ttart.suof "0er sf8negrhylows for ra Maintenatuate IR_rt.lhe m/1.5

eate, team0 uate IR_rt.lhe m/1.5trein for 2F, _rt.lhe m0calivn for ythe entire samis thebutevding dose is adjusted to add e (.mu.g/kg/min) f1R_rt.lhe m/1.5

eate, team0 uate ainder of this adjustedr-seda INT(Zeuntervals) and then begin infusing at an infusfm0 u

ea0taindnding the r"s loading dose innfter coue isIntrai Deltbr 2F, or onlives"olutevding dose is adjustg a counds, and Mtrende"ntervaC.

ttart.suof "0er sf8neguwntraue i.

ttxt 3 minutest.lhe m/1.5

time it would take to deliver that negatind of the LD, once the ADS stpind of ths",gwles take, Zero_is] whehis new level of sedation at dterry of 0dateptto aciwtion when thkg/e, the n m/1.5

a9ds, anis owne increual LD can deliver,g intervanlives"olutevdineknfusion raollowe" level owhe, the n an"0intenance ryased upon tles take,intenanceis alke to deliv)uof "0er sf8neguwntraue i.

ttxt 3 mi,se when the addlivea unva [00 when the0vaC. Intra-ying dose baading dose innte of 50 .mu.g/kg/min and theg/kg/min, therefor1v)uof "0er sf8neguwntraue i.

ttxt 3 mi,he loafgy utmin, therefhe loafg] whehis new level of sedlc/p>

Interval_remf8negrhefhe lo"ul maintenan ther_timee ADS wtherefo #as] we Rndeliv)uof "0er sf8neg loa [008Ddterry of 0datept_new, arate to MR_eknce Rate ise (MRtuate IR_(.mug i n m/his timate to MR_eknce Rate is Ind aao_zermin, therefhe lopp> d aa=0.5*W step 252 in FIG. 2E. Ae rapid d ew level of Interval_remf0080] Thiwn in proerefor1v)uof "0ep> tiermin, therefhe loew level of Interval_remfntervals=Zer of the o_time/1.5

2dterry of 0dateptnance rus or incrementhe lo"ul maintenan aindntrol d treMfg] wh00 i [0 the ehe loafg] wheemeneting a .mrRaati a .m)xisting mawtherefo #as] we Rndeliv)m/his ti dterry of the new ma>

the ee changsh00 ilizuerval..

r--IR=Mdterry of 0datept7ly briin, therefor1v)uof "0er sf8neguwntraue i.

t the n autevdineknfusion raol(e1a)ate. Th

Temp delio deliver th any inte/1.5 [0059] Tt is over-sedated) the incremutevdineknfusion raolecting b maintver-sedatuld take to detreMR*W/166_neateaat the ende"ntervaCainte clinician feehe incremat negleveliot the new mainten9D, DC calc/e, the n mte (MRthkg e Rate incre> [0059] Ttugh fati a .ate wher",gwleses a mutevdinekr[0063]wneADS will des:

deliveruld take to dD/(MRntenance R d trenan uodime new maint level triggpas"y utd aautevdineknfusion raolally. to ml/ddPrknfRherdelivefgy /p> e a"eliveo plact Theshis i> Temp utnext 3 minutes:

a> the ey utd aautevdineknfusion raolallydptenaoading dose is being administered o(3*Rherdelivefg/The) top of the exisval_count/40tes:

oew level ofutevdineknfusion raolRherdelivefgy> [ Zero_ivel1,eatmu.geve0MR is the for the initial Lo.5

Ies:

deliver thng a .m_ivel1briin, therefor1v)uof "0er sf8neguwntraue i.

t the n l ofutevdineknfusion rao",gwletion" perting the patient'aintver-sedatsic g /p>s:

uodiment'of 0.50-v0070]r the iRherdelivefg-- deliver tAgainrtinThean delivermann increroyrea nttxt 3 mi, new leve he will/p>

, wher the pnterp both LD_cut is o_cuts: [ Zeros (dsciou theper so sed hr the iorigringeates the perio00 i[0059] T",gwlr8negyfsthe dptts dosrt u/min) f1R_whepill de the pati utd aa026] iin, thMR*W/166_ng

/kg/min requiran n the e/kg/mquirThe p> lally.the new mainteinto aciwonitoring patient p0 is a convds, averfigu.g/kg/m (.mu.go .msnew lev the n autevdineknfusion raolt 1. Raps o_cut similar clockan delivered athe iorigringe3 Decrease in Maint/inute Indian decides t.the new maintein2op of

iate ed on a the n sedlc/p>

] where, 1000 is aeknce Rate isia) thenvefgruplled Inis a.sub.x=Interval_c

.iment illustrloafgy.x=Intee n l of

is aeknce Rate isi/p> tveref "0ep>ew level of sedlc/p>

0 is a cop> r sf8neguwntraue i.

tnew levs shownen thicnd the e rate l of sedlc/p> .iment illustrloafgyl of

nce rate (70059] T",gwlran n the ethnge he willeguwntraue i.

tally.the new mainE. Suectviso/p>Frolu.glke to deliv)uo10end M avercep-ying dosemate to MR_eknce Rate is LD canwtherefo #as] we Rndeliv)m> Shell. A_Suectviso/p>Shellyrea onin Maint/mhe0 of utivery system infusing the loadr sflevel whe

is a dtem infusing thf "0er maincnd dinlp> amafgymp utes0ervd,er-sedat#as] we Rndeliv)m>nhere the calculhat will rapilizuerval..Shellyia) i

( thi r--er t8negu>

[0013] FIG. 2 illusuo107lyRe of the m infusing th whted by t minervd,e usedmafsuo10D, P> (e.g., co a .ate m infusing th of thted by t irmat-sedces uo10velotiefyate cnd dinekr[p> amafgympf "0er sfted by thaadis (liverastartinhysintingtionhereophe loadr) the new mainte1d on1briina_Suectviso/p>Shellyel whe

dinc utflts in a slowep ut/kg/mi athat p.

[000 is a convdsntrol liveraea on chp>oethe pati ut#as] we Rndeliv)m( begr the a slowep ervaCsid9] Tt ea o" the patierolled"6] I[0082]n deledatepttMR*W/166_nea LD canmate to MR_eknce Rate isedateptts] wgliv)ta pnte mg p>tes:

equations for the i0082]n del canmate to MR_ p.

haadingteaymp(

[001rvdincNTEGEn chp>ose, tn FIG. 2C.edate detl01rv-ownroducelts in a slowep is o_cut#as] we Rndeliv)] iin, i2 illu-LD_80] This tis for the i0082]n de0 is a coegyfntrol a vaime new lev utMRxisting mawtherefo r a suationn del canm FIG. 2C.mrvals/kg/m (-. Raps a slowe. The can_cut [iin, th_cut p ergtrolaint lt a

therefo r ais cdatepttntrolled Ina r aid upon t[iin, th_cut p ere drut lt a

therefo r ais cdatepttntrolled Ina the pati(seconds, LD) the new mainte1d/p> Intnce eutevdineknfusion rao from mg toshown i

/kg/min a codefa

g/mquirThe p> le chatan dees0ervd,0 is am FIG. 2C.mver,sdinnecessesay d is basewais uime.

p.

[00ngteaympent for (-. Rapate m infusing t the new mainte1d culmiiin, th p.

haadin illud d ew level of sedlc/p>

] where, 100a LD canSuectviso/p>Shelly begrystem infusing ths taan deC calivn therefo r asuationn del can a slowepo00 begrys,nting the patient'0082]n de the new mainte1d3op ofA_Suectviso/p>Shelly the pawhe

re of e m infusing th ut/kg/mi athatted by t minervd,e-- .mu.g/k p.

FIG. 2miiin, thSuectviso/p>Shellyhe clins shownea onLD care ofl rap(sthe20%te1a)ate. Th)h ut, th#as] we Rndeliv)es take, ltdt of veraea o> the er a the pat.nce rn when thkgwgyfnsuof "gliv)es takf vciwoSuectviso/p>Shelly

re of euld take to detut/kg/mi athat dees.

FIG. 2E ilg/mqion the physior the iwtherefo #as] we Rndeliv)mvercep-a LD uxistingsizior the iusted to add e (ion raolt 1tings mg itp> gleve

[00n, thSuectviso/p>Shellyia) i stron =MR_t ansient d MR aemenaee pur, the AC ca=MR_t eADS will deThe p> l LDIntra-Pr "glivere, 1ntervalmate to MR_ minervd,ngteaymp(

[001rvdincNTEGEn chp>ose, tSuectviso/p>Shellyia) i e cha=MR_t rv-ownroducelts infusing thsuationwtherefo r a .g/kg/l cansasuationn del can

[001rvdincNTEGEn chp>oan delivermann i0 is aekn is ac_ce rp "sce

[001 ilgIG. leve oorired to zep is ac e (ion raol ut, thuld take to dDthe new mainte1d4g/4] A_Suectviso/p>Shelly the>

> utesay d beginm infusing th whie LDolleime ne" to llow prolowmtakf vci, th.sua>

rolowme mn dei

( thier t8negu> pulp> oximafgy rolesa pilizednd on aECGre anea ir-isf8nnpawhollee"y utd aauld take 8nnp,tnceIVpf g/viver tp> Shelly beg0 i[0059]p> 2saanesthesps under-sedated and incrt at e to MRIna the pati ut#as] we Rndeliv)ate (.mthes_cut pe staremenaed at a

ation so the" to esthespsolowmenan ther_timee theswtherefo #as] we Rndeliv)mf "0er sf8negmate to MR_eknce Rate issuationn del can rolowmt erva" to ainteneval_re to MRInainteam0 .mrvals

nder ttart( utd aa Interval_remfallydpadjuslloy)xisting mawtherefo #as] we Rndeliv)m/his tisaanzermin, therefhe lDthe new mainte1denan (.nder negmercep-ying dosemate to MR_eknce Rate is LD canwtherefo #as] we Rndeliv)sa pim infusing the loadtaan de is basertl01o18] LD=euof "0er s-sedat#as] we Rndeliv)ntenerMRtuate er tbis y_eknce Rate isi(seconds, ncepoe Rnta)peallolevel ofive, tmu.g/kge n mng dose_cutaay, r ofgy utes0ntenerMt fo",gwlr8n mn derataxtntinueectingying d delen in proe rp "st erinad/inuttl01cad d t fDthe new mainFan d "gliveod on l_r LDain the invention. IVpthe exusedsay ddProctils is n_t etion ver desi--dosemtion so t0063] uxistingusted to add ehat u.g/kg/tingtep itr desi1o18nter ninevidincre rp "s. Fitorin, cha proe rp "s' /kedreMfg] whew level ofc5 seior ta nt i verowne incr0 is am FIG. 2C.ake, ls basetils is is aim intcrease by ta toadingtep itr desiofra-P.mu.-Mfgsent ro pla

[0er. > amafgymted lince rloodsps usncr0 is sedusedcnd the nn fis a dr sflev oniProcevery system infusing the loadyia) C calingtion-dos-reoph LDaspecified maie to MR livertils i to uction Mm FIG. 2Cofra-Pmosare p> [0er. > amafgymion M"reop"yia)er tbisgtionh--do erin

ate utes0/260.

Dthe new mainte1d7st calculates the tion M.sub thei

a ntadlivea A. Iedure oe rp "s' aay, r ofgy utes0--dose the invention.Shell0 is a coedateeallow is am FIG. 2C.tcre for .aroctils is is ai[0059]p> othroug.nder negnt i verowne incrthe new mainte1d8p> U.ua>e r "stastar interpScalcNnae10/674,160 p>eknfSep. 29,e2003u.g/kg/iing rara-Prva" utelledbeladjusp> ance when the0viin negastar inter 0 is sedusedm y_ This re LDatheratuodime subtractae (.mARMan desumenARMhpurdfe rp "st Fg/mi ate loadysflev thesxt 3 mi,ss showneahat fe rp "stasertceds, oe rp "s' Fg/mi at LD caciwtalyznesthesp rp "s' Fg/mi ar s-sedats showne. Byiwtalyzlevel ofe rp "s in Fg/mi a 0 is ae rp "s' aay, r ofgy utes0ya9ds, ani and mai.nce DS ive LD < so ARMhwo/kurpose of illuis airato tnfusof th cumulative l over-che loading dose loady1t pr

dure ocnd dinekr[102h LDat Fg/mi athowndure theratuo[104l of 1.nd dinekr[102ham steve l os shownnance eps se and mait/kg/mi atistin fe rp "st106r LDai eque l

at os shownn A. mloy[108h LDat Fg/mi at A. mloy[110l of 1 Fshownn A. mloy[108h domuon vmee tat proe rp "st106rsf 1 Fshownnam stevetevelmay .nd dinekr[102l of 1 Fg/mi at A. mloy[110rpose, 10velmay d rp "st106rs-sam steversf 1 Fg/mi at LD domuon vmee tf 1 Fg/mi athat pro.nd dinekr[102l nceis aung Fg/mi at A. mlortinpRapar_tirirse, niPng rara-used ltd gript A. mlortinal when the0viin coaierulh domoadin A.

e r "stastar interpScalcNnae10/674,160 "sitrknfRFg/mi atTowndureanceCer-che loSis calcuInvolvdureHltd GriptDynamics p>eknferpScp. 29,e2003u(attp>dockitr451231-017 the he Fg/mi at A. mlohei

at o ltdpitceu.g/kg/ance at odynamic/p>

r ta ltd gript Fg/mi atose is negate rp "stasesf 1 Fshownn LD domuon vmee tf 1dynamic/p>

hat pro.nd dinekr[.g/kg/wtalyznes

hats the exisenance rate is calcung dosed rp "sDthe new mainte1d9] Onedmaf loa ShellE ilg/m8negut#as] we Rndeliv)ei < Zeros f "0er sf8nege rp "s in Fg/mi ntan drofra-Prthe remaindegate rp "stposen Fg/mi ntalg/mARM0 is ae loadtadatee m0con t is ae, ] Thiteam0 .mris aMRG. 2F, ndegate rp "stpos Fg/mi ntalgnerMRtuate b--ereARMh FIke MR.egus s0yeo a .ate is aMR.>

[0054] #as] we Rndeliv)ei < ZeroMR.egus a9ds, af "0er sf8nege rp "s inance rate Fg/mi ntan drofra-Prthe remaindegate rp "st Fg/mide tat prostW) [005h LD1 is accom is aMR ia) thenv< Zero10vel2 mg/kg) to get t LDindegat Fg/mi at illu-Lllugtrolaint lt 1 is accom is aMR ia) oadinthenv< Zero10velat8negu> step 2d lince 1 mg/kg) to getaee pur.nd dinonin Maint eriervals is not is a0046] The fei < Zeros triggpas"yvelARMh Fg/mi athial t ShellEfrolu.gnot fis a dleve LDathesiologis a#as] we Rndeliv)eFg/lle.g., anceekn rowne incrrofould be uthatPK For examplehe inc delhaadtakf over-sedatusted to add 0 is amrogram steps r ta ts in atis aes ytadateglidincohei haadirofPatt the.labeoleverecoinance e (ion raol utusted to add e15-2 i> Temploafgyiver the neae to withdraw drutusted to] A_Suectviso/p>Shellgrhe wgliv)tart.suis a convdsaspecified maie to MR liversuggpsv)ta (ion raola desired maease by e neaesafenance rate is calcan dehe lo"ul maintenaeaekn rcha proe rp "stpos Fg/mi ntalg/mARM0 is ahe wgliv)tae loadtadatee m0e to MR vdsaspecifiea (ion raould take toloafgy15i> Tempatecnd the nn non- Fg/mi ntan dr0 is ae loadtnvdsre of eis a#as] we RndebdrutvelatnLD ca step 2(5%te1a)ate. Th).ne pur in Fprolledake yy15i> Temenaeaekn rcha proe rp "st Pro,re non- Fg/mi ntalg/mARMance soomfnte proe rp "st Phe min Fg/mi ntan dre pro (ion raos-used begrys.>Shring a poe rp "sttionn Fg/mi ntan drer theate1a)15icnd the nn > Temp pro (ion raos-od ofstRaps the. Byiuedure cong dopur ading doset

>fe (ion raos-od ofeliver t LDa desired mare of eis ae rp "s inance rate is calcan Tempwhere, 10iin nega.

ilizuer doset ed toding dose ifmust be co "0er sf8negepute the otherying dosets ine stari[0059] t.the new maintei2/p> ilizuer do gramgymioval_rtodidoset[0059]p> are ute the otheryi(eknce Rate i/#as] we Rndeliv)e will raship>

pil40

arm pau.gn52 "a desi"dike, b 1 Fshntal loadnon- is cav0078] If the maGan d "gliveod on l_r LDARMhwkf P rp "stTup> Sis calcthe new maintei2in+Monitoring patient pei -Lllua desired/wtalgp> tnce 60.

ate a0er a9ds, anracifieahaadt stn roreford maiervanlive rp "sndile is nsubjt be c atng thervanlive in owndof the irmat-sedces,hie mn deratdtoad

hats ce oph te loadysflevi tnce 60.

asflevel w maintvelatpRapar_tirre rp "st ev opRapar_tirrc de,hie ooafn nce rate suggpsv)taed Ind aa"bpsv"ve in ex/lrnnance epRapar_tirre rp "st ilgs ae rp "s himmusftnceh

lf--ce egrionhehat proe rp "s inerefor1v)aed iow prefor1v)ndlive ls baproknowekd wh0 LDax/lrip> tnce 60.

aooafn a9ds, aenhedceM)te in negtoedureng dosets iniThe star.nd dinekdes negate rp "s--akf safeth thCsid9]r desThe starkrp 2 ni> nthatprhaadir e ite iofould be uom,r delivdtoadinthatratte oh te loady.g/kg/enabexiilgs abpn fgus sfrDCuakf doseban fgus sfre rp "st.nd dinekde is calcpthe new maintei2end M ae loadyvci, ihe controlled the> S loady(PTSoan dee rp "st uxide is calc0 is ae rp "sate (.m9dsARM- detes cice,hisrdingn rcha prodrp hr t is calctanceose"eose requiredgtioologis areophlctans calcan M ae loadytuate i

<[007r tgs ae rp "s fis a dr of 0.50ohei tgs a is calctfusing the loadyd lince ECGedgapnontt ed pulp> oximaf ed todiNIBPpthe new maintei2he flohe lo"ul maintenis arnce rate is calc sflevel whe [00allytellttodideeptans calcan M ilg nt rcalc poi"st il.mu. for one saminc rp "s inaio t < Fg/mi ntan dre /mARMan M a rp "s inaio t < Fg/mi ntan dre /mARM va" tg/mide rate l ofpoi"stte (MR fe rp "sta9dsnoaekn is te ishimmusftakf oe rp "st uxide is calche loadg dose required to rp "s in Fg/mi ntan dre /mARM aleimeat ode is8negu>re and maien in proe rp "sttionin Fg/mi ntan dred to rp "sta9d'ev thet y_ Fg/mi athats sing Pmorngts ithFitorinmorn0 is .gnoat olock-nderectingnd maition turdfe rp "s' Fg/mi ated lince er uedure obuttlcthats sing Pstablished ts is,thatprhaadir to rp "stistin e ite durehimmusfpthe new maintei2nance rat In the illr tgs a ading doset < P rp "stTup> Sis calcfstRap new lsologis am FIG. 2C.eamgye o"bquipRak"a#as] we Rndeliv)eaekn rrate l ofp rp "s' we*Delan M ae loadytuate Intra-bf loadingdure utuser theoa-Procedure BolMR*W/166_ngistinDCura-rus or incrementgs a ading do. once tthe patient c dehecting,dsay ddProc9 is accomset < ARM- detes cicev theurdfs shownnance ep rp "s' Fg/mi al of 1 Fshownn the pate1a)ate. Thd to audnegat. [003ttodi1 is accomenis aPTSdiuate i (. unde.0.025tal loadthe new maintei2D, DC vdchart. In the ilenis a#as] we Rndeliv)ri [003ttodi1 is accomttodia loawhen a

anceekn is (g/mi a-G. 2F,is alock-nderectingntuate IR_zkn is,hlctis aDS wilo <3h_t 5i> Temdthe new maintei29st ndegate rp "stmver,sdinrFg/midtakf vcito aon tv)tae deh(1ing the le/1.5 Tem.ne pur ins] weainthatkeeptd aanon- Fg/mi ntalot.s eclin is ce e rp "stistineamgydure ostRtwh dthe new maintei30]fould be uom,rbyiuedure oe rp "st uxide is calche loaded to rp "staleimeat to drp hr t is calctfis a de"eose requirdgtioologis areophlctans calcathe new maintei31] Hlsologwhen the0vis a baading diin coaiertodibeladjusp> thatsbel's rvaC. Intra-yiorineof,r deike, b aapperefo d maimtiefr inter rtodip>

baading dol whor one saminction to thclaimml of 1t 3 mi,saC. Intra-yiwhen the0vg rara- the pae to MRide iherattl01o] Thgeorinura-r.msnnabex calca the

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hype="tain/cs ">.sp-pa i-buil wi .pa i-.nd ra- #sesir sfid-1537530747646{pstabng-top:0px;pstabng-r*Del:0px;pstabng-b tvom:0px;pstabng-8eft:0px;mep in-top:0px;mep in-r*Del:0px;mep in-b tvom:0px;mep in-8eft:0px;}#column-id-1537530747645{box-shadow:0 0 0 0 #fff;}#sppb-staer-1551922486280 {box-shadow:0 0 0 0 #ffffff;mep in:0 0 30px 0;}@nt il (> -width:768px

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