Systems and methods for controlled delivery of analgesic and hypnotic agents

Patent metadata

Field	Value
Publication number	US-12377214-B2
Application number	US-202117398370-A
Country	US
Kind code	B2
Filing date	Aug 10, 2021
Priority date	Apr 18, 2016
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The invention involves the administration of clinical anesthesia. Particular embodiments provide systems and methods for controlled delivery of a combination of an analgesic agent and a hypnotic agent. More specifically, the invention involves closed-loop control systems/methods for automatically controlling the administration of a combination of a hypnotic agent and an analgesic agent in a clinical anesthesia setting which incorporate feedback based on one or more indirect measures/indicia of analgesia. The invention further includes such control systems/methods that account for limitations of such indirect measures/indicia of analgesia.

First claim

The invention claimed:

1. A method for controlling a first rate of infusion of a hypnotic agent uP into a subject and a second rate of infusion of an analgesic agent uR into the subject, the method comprising:
receiving, at a computer processor, a measure representative of a depth of hypnosis (DOH) of the subject is selected from a group of indices consisting of a WAVCNS index or a BIS index;
determining, by the computer processor, a first control signal (or value) for each of a first series of time steps to control the first rate of infusion of a hypnotic agent u P into the subject and determining a second control signal (or value) for each of a second series of time steps to control the second rate of infusion of the analgesic agent u R into the subject, wherein determining the first control signal and determining the second control signal are both based on the measure representative of the depth of hypnosis; and
outputting, from the computer processor, the first control signal to a hypnotic agent administration actuator at each of the first series of time steps, to thereby control the hypnotic agent administration actuator to inject the hypnotic agent into the subject at the first rate of infusion of the hypnotic agent u P and outputting the second control signal to an analgesic agent administration actuator at each of the second series of time steps, to thereby control the analgesic agent administration actuator to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent u R ;
wherein the first series of time steps is the same as the second series of time steps.

2. The method of claim 1 , wherein determining the first control signal and determining the second control signal comprise determining the first and second control signals, such that when the first and second control signals are output to the hypnotic agent administration actuator and the analgesic agent administration actuator, the first and second control signals cause the hypnotic agent administration actuator and the analgesic agent administration actuator to inject the hypnotic agent into the subject at the first rate of infusion of the hypnotic agent u P and to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent u R to thereby cause the measure representative of depth of hypnosis (DOH) of the subject to track a reference depth of hypnosis DOH ref .

3. AThe method of claim 2 , wherein a response of the second (analgesic agent) control signal to a DOH error (between the reference depth of hypnosis DOH ref and the measure representative of the DOH) is dominant at higher frequencies relative to a response of the controller for the first (hypnotic agent) control signal to the DOH error.

4. The method of claim 3 , wherein a response of the controller for the first (hypnotic agent) control signal to a DOH error (between the reference depth of hypnosis DOH ref and the measure representative of the DOH) is dominant at lower frequencies relative to a response of the controller for the second (analgesic agent) control signal to the DOH error.

5. The method of claim 3 , wherein determining the second control signal comprises implementing a second controller, the second controller having an analgesic agent amplification A R (ω) of less than −3 dB in circumstances where DOH error (i.e. a difference between the reference depth of hypnosis DOH ref and the measure representative of depth of hypnosis (DOH) of the subject) varies at a frequency of less than or equal to ω=10 −5 rad/s (i.e. A R (ω)<−3 dB for ω≤10 −5 rad/s.), where analgesic agent amplification A R (ω) is equal to the power spectral density S R (ω) of the second (analgesic agent) control signal over the power spectral density S E (ω) of the DOH error, the second (analgesic agent) control signal is expressed in the units ng/kg/min, the DOH error (between the reference depth of hypnosis DOH ref and the measure representative of the DOH) is expressed in units of a DOH index and frequencies are expressed in units of rad/s.

6. The method of claim 2 , wherein a response of the controller for the first (hypnotic agent) control signal to a DOH error (between the reference depth of hypnosis DOH ref and the measure representative of the DOH) is dominant at lower frequencies relative to a response of the controller for the second (analgesic agent) control signal to the DOH error.

7. The method of Claim 2 , wherein determining the second control signal comprises implementing a second controller, the second controller having an analgesic agent amplification A R (ω) of less than −3 dB in circumstances where DOH error (i.e. a difference between the reference depth of hypnosis DOH ref and the measure representative of depth of hypnosis (DOH) of the subject) varies at a frequency of less than or equal to ω=10 −5 rad/s (i.e. A R (ω)<−3 dB for ω≤10 −5 rad/s.), where analgesic agent amplification A R (ω) is equal to the power spectral density S R (ω) of the second (analgesic agent) control signal over the power spectral density S E (ω) of the DOH error, the second (analgesic agent) control signal is expressed in the units ng/kg/min, the DOH error (between the reference depth of hypnosis DOH ref and the measure representative of the DOH) is expressed in units of a DOH index and frequencies are expressed in units of rad/s.

8. The method of claim 1 , wherein:
a low frequency range of interest for the context of clinical anesthesia is w 1 =[0.0001 rad/s, 0.006 rad/sec] and a high frequency range of interest for the context of clinical anesthesia is w 2 =[0.006 rad/s, 0.08 rad/s]; and
a ratio of an amplification integral of the hypnotic agent amplification A p (ω) over the high frequency range w 2 to the amplification integral of the hypnotic agent amplification A p (ω) over the low frequency range w 1 (i.e. I P (w 2 )/I P (w 1 )) is less than a ratio of the amplification integral of the analgesic agent amplification A R (ω) over the high frequency range w 2 to the amplification integral of the amplification A R (ω) over the low frequency range w 1 (i.e. I R (w 2 )/I R (w 1 ));
where the hypnotic agent amplification A p (ω) is equal to the power spectral density S p (ω) of the first (hypnotic agent) control signal over the power spectral density S E (ω) of the DOH error and the analgesic agent amplification A R (ω) is equal to the power spectral density S R (ω) of the second (analgesic agent) control signal over the power spectral density S E (ω) of the DOH error.

9. The method of Claim 1 , wherein:
a low frequency range of interest for the context of clinical anesthesia is w 1 =[0.0001 rad/s, 0.006 rad/sec] and a high frequency range of interest for the context of clinical anesthesia is w 2 =[0.006 rad/s, 0.08 rad/s]; and
a ratio of an amplification integral of the hypnotic agent amplification A P (ω) over the high frequency range w 2 to the amplification integral of the hypnotic agent amplification A P (ω) over the low frequency range w 1 is less than 20 (i.e. I P (w 2 )/I P (w 1 )<20);
where the hypnotic agent amplification A P (ω) is equal to the power spectral density S P (ω) of the first (hypnotic agent) control signal over the power spectral density S E (ω) of the DOH error.

10. The method of Claim 1 , wherein:
a low frequency range of interest for the context of clinical anesthesia is w 1 =[0.0001 rad/s, 0.006 rad/sec] and a high frequency range of interest for the context of clinical anesthesia is w 2 =[0.006 rad/s, 0.08 rad/s]; and
a ratio of an amplification integral of the analgesic agent amplification A R (ω) over the high frequency range w 2 to the amplification integral of the analgesic agent amplification A R (

Assignees

• Univ British Columbia
• Neurowave Systems Inc

Inventors

• Dumont Guy
• Van Heusden Klaske
• Ansermino Mark

Classifications

• A61B5/7203

  for noise prevention, reduction or removal · CPC title

• A61B5/4821

  Determining level or depth of anaesthesia (based on movements A61B5/1106) · CPC title

• A61M2230/08

  Other bio-electrical signals · CPC title

• A61M5/14

  Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor · CPC title

• A61M21/00

  Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis · CPC title