Systems and methods for controlled delivery of analgesic and hypnotic agents

The method according to aspect 1 or any other aspect herein 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 uP and to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent uR to thereby cause the measure representative of depth of hypnosis (DOH) of the subject to track a reference depth of hypnosis DOHref.

A method according to aspect 2 or any other aspect herein wherein a response of the second (analgesic agent) control signal to a DOH error (between the reference depth of hypnosis DOHref and the measure representative of the DOH) is dominant at higher frequencies relative to the response of the controller for the first (hypnotic agent) control signal to the DOH error.

A method according to any one of aspects 2 to 3 or any other aspect herein wherein the response of the controller for the first (hypnotic agent) control signal to a DOH error (between the reference depth of hypnosis DOHref and the measure representative of the DOH) is dominant at lower frequencies relative to the response of the controller for the second (analgesic agent) control signal to the DOH error.

A method according to any one of aspects 1 to 7 or any other aspect herein wherein:

• a low frequency range of interest for the context of clinical anesthesia is w1=[0.0001 rad/s, 0.006 rad/sec] and a high frequency range of interest for the context of clinical anesthesia is w2=[0.006 rad/s, 0.08 rad/s];
• and
• an amplification integral IP(w1) of a hypnotic agent amplification AP(ω) over the low frequency range w1 is greater than or equal to 0.2 (i.e. IP(w1)≥0.2), where the hypnotic agent amplification AP(ω) is equal to the power spectral density SP(ω) of the first (hypnotic agent) control signal over the power spectral density SE(ω) of the DOH error, the first (hypnotic agent) control signal is expressed in the units mcg/kg/min, the DOH error (between the reference depth of hypnosis DOHref and the measure representative of the DOH) is expressed in units of a DOH index and frequencies are expressed in units of rad/s.

A method according to any one of aspects 1 to 8 or any other aspect herein wherein:

• a low frequency range of interest for the context of clinical anesthesia is w1=[0.0001 rad/s, 0.006 rad/sec] and a high frequency range of interest for the context of clinical anesthesia is w2=[0.006 rad/s, 0.08 rad/s];
• and
• an amplification integral IR(w2) of an analgesic agent amplification AR(ω) over the high frequency range w2 is greater than or equal to 1 (i.e. IR(w2)≥1), where the analgesic agent amplification AR(ω) is equal to the power spectral density SR(ω) of the second (analgesic agent) control signal over the power spectral density SE(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 DOHref and the measure representative of the DOH) is expressed in units of a DOH index and frequencies are expressed in units of rad/s.

A method according to any of aspects 1 to 9 or any other aspect herein wherein the measure representative of depth of hypnosis (DOH) of the subject comprises a WAVCNS index.

A method according to any one of aspects 1 to 9 or any other aspect herein wherein the measure representative of depth of hypnosis (DOH) of the subject comprises a BIS index.

A method according to any one of aspects 1 to 11 or any other aspect herein wherein determining the second control signal comprises determining the second control signal, such that when the second control signal is output to the analgesic agent administration actuator, the second control signal causes the analgesic agent administration actuator to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent uR which causes a predicted analgesic effect site concentration Ce to increase by an amount which is proportional, to within +/−10%, to a step increase in the measure representative of depth of hypnosis (DOH) of the subject.

A method according to any one of aspects 2 to 12 or any other aspect herein wherein determining the second control signal comprises implementing a second controller, the second controller having an analgesic agent amplification AR(ω) of less than −3 dB in circumstances where DOH error (i.e. a difference between the reference depth of hypnosis DOHref 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. AR(ω)<−3 dB for ω≤10−5 rad/s.), where analgesic agent amplification AR(ω) is equal to the power spectral density SR(ω) of the second (analgesic agent) control signal over the power spectral density SE(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 DOHref and the measure representative of the DOH) is expressed in units of a DOH index and frequencies are expressed in units of rad/s.

A method according to any one of aspects 1 to 13 or any other aspect herein wherein determining the second control signal comprises determining the second control signal, such that when the second control signal is output to the analgesic agent administration actuator, the second control signal causes the analgesic agent administration actuator to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent uR which is greater than a lower bound uRbase for all time steps in the second series of time steps.

A method according to aspect 14 or any other aspect herein wherein determining the second control signal comprises bounding an average, over time, of the second control signal in response to noise in the measure representative of depth of hypnosis (DOH) of the subject.

A method according to any one of aspects 14 to 15 or any other aspect herein wherein determining the second control signal comprises implementing a second controller subject to the constraint of equation (16) described above.

A method according to any one of aspects 1 to 15 or any other aspect herein 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 uP and to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent uR to thereby implement robust stability of the measure representative of the depth of hypnosis (DOH) of the subject despite non-linear interaction between the hypnotic agent and the analgesic agent.

A method according to aspect 17 or any other aspect herein wherein determining the second control signal comprises implementing a second controller subject to the constraint of equation (19) described above.

A method according to any one of aspects 1 to 17 or any other aspect herein 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 uP and to inject the analgesic agent into the subject at the second rate of infusion of the analgesic agent uR to thereby implement robust stability of the measure representative of the depth of hypnosis (DOH) of the subject despite inter-patient variability over an entire definable subset of the population.

A method according to aspect 19 or any other aspect herein wherein determining the second control signal comprises implementing a second controller subject to the constraint of equation (17) described above