JP2009540890A - System for controlling anesthetic administration - Google Patents

Abstract

  A system for controlling the administration of a respiratory function inhibitor or a mixture of drugs to a spontaneously breathing patient comprises an index-coupled automatic titration for the respiratory function inhibitor or a mixture of such drugs to the patient (1) or A drug delivery unit (3) suitable for continuous automatic titration and a measurement signal (20) related to the respiratory state of the patient (1) are received, and a control signal (27) is sent to the drug delivery unit (3). A control device (6) for outputting, which provides sufficient sedation and / or analgesia to the patient by maintaining the measurement signal associated with the respiratory condition in a predetermined state. .

Description

Background of the invention
1. FIELD OF THE INVENTION The present invention relates generally to a system for administering one or more respiratory function inhibitors to a patient breathing spontaneously and related procedures. More particularly, the present invention relates to a configuration for sedating a patient and relieving pain, discomfort, and / or anxiety during a medical or surgical procedure. The configuration determines and implements an optimal dosing profile based on the respiratory gas content in the body and / or the monitor expressed as respiratory activity and / or estimated respiratory drive. The present invention is capable of achieving effective patient sedation while minimizing the side effects caused by drugs under open and closed loop operations.

2. Description of Related Art Anesthesia is a state in which sensory ability in the body is reduced. It is a reversible pharmacological condition caused by the administration of anesthetics. Proper anesthesia during medical treatment ensures patient loss of consciousness, analgesia, and / or muscle relaxation.

  According to the International Pain Society (IASP), regular reassessment of drug administration is required during medical and surgical procedures. Coupled with temporal changes in responsiveness, obvious individual differences in response to drugs and surgical stimuli require personalization of drug delivery. Adjustment of the dosing profile for the patient is based on an ongoing process of effect assessment and dose titration. Its purpose is to optimize the desired effects (eg, analgesic, mental stabilization and sedation) while minimizing unwanted effects (IASP Special Review Board, 2005). The present invention relates to a management system and a management method for effectively solving these problems.

  Sedation techniques are currently useful for achieving patient analgesia and mental stabilization during medical and surgical procedures. “Conscious sedation” and “supervised sedation management (MAC)” are defined as medically controlled hypoconscious states that can maintain the defense reflex. Sedated patients continue to breathe spontaneously and maintain the ability to protect the airways. Depending on the depth of sedation, patients can respond to verbal instructions and tactile stimuli with different degrees of intentionfulness (Novak, 1998). During conscious sedation, the physician manages and administers sedatives and / or analgesics that calm the patient's anxiety and ensure analgesia throughout the diagnostic and therapeutic procedures To do. Such pharmacological suppression, which moderates consciousness, is intended to facilitate successful performance of medical procedures while achieving patient comfort, mental stabilization and cooperation. On the other hand, MAC enables the safe management of the deepest sedation that exceeds the sedation obtained during conscious sedation (ASA Relevant Value Guide, 2006).

Conscious sedation and the use of MAC are widespread for, but not limited to, the following therapies: That is, endoscopy (gastrocamera examination, colonoscopy, endoscopic retrograde pancreatography (ERCP), etc.), bronchoscopy or fiberoptic intubation, cystoscopy, extracorporeal shock wave kidney stone fracture (ESWL) ), Drainage of chronic epidural hematoma (combined with local anesthesia), debridement of trauma / burn, abscess drainage, virtual probe plastic surgery, therapeutic radiography, oocyte extraction for artificial insemination, dentistry It covers a wide range of surgical practices (combined with local anesthesia) and ophthalmic procedures (combined with posterior ocular block).

  There are several factors that make conscious sedation and MAC attractive compared to general anesthesia. Low drug and device costs, long-term monitoring following treatment, and short patient recovery time maintain moderate clinical costs. Conversely, general anesthesia and subsequent post-anesthetic recovery has a significant impact on clinical costs related to equipment, medications and human resources. In addition, causing prolonged loss of consciousness in the patient adversely affects the duration and quality of recovery. Patients treated with conscious sedation and / or MAC usually discharge sooner than those who have undergone general anesthesia. On the other hand, conscious sedation and MAC are not suitable for all surgical treatments. For example, markedly invasive surgery usually requires general anesthesia to be performed, delaying the patient's preparation to go home.

A number of different drugs can be used to sedate the patient, and higher dosage results in general anesthesia. Examples are opioids (such as remifentanil, alfentanil, fentanyl, sufentanil, and meperidine), benzodiazepines (such as midazolam, diazepam, and lorazepam), propofol, and ketamine. In the clinical situation, sedatives and analgesics are administered by oral, rectal, intravenous, or intramuscular injection. The opioid is administered intravenously. When the sleeping pill is a volatile drug, it is administered intravenously or by inhalation. Regardless of the method of administration, most of these drugs have significant respiratory depression. This depends on dosage, administration profile, patient sensitivity and health. High dosages and / or fast dosing rates can determine dangerous dysfunction of respiratory drive, ultimately leading to apnea and death. Furthermore, respiratory inhibition causes an acidic condition in the body due to excessive CO ₂ levels. This phenomenon is referred to as respiratory acidosis (expressions referring to the same include high carbonic acidosis and carbon dioxide acidosis). Severe respiratory acidosis can be life-threatening if a rapid increase in PaCO ₂ is associated with dangerous hypoxemia and acidemia. In fact, the American Society of Anesthesiologists (ASA) defines respiratory depression caused by drugs as a root cause of morbidity in patients who voluntarily supply oxygen (ASA Special Investigation Committee) 2006).

  From what has been explained so far, it is clear that sedating a patient represents a trade-off between pain relief and anxiety control and inhibition of respiratory drive, obstruction of airway protection and loss of consciousness. Therefore, it is not surprising that drug-induced breathing disorders, blood deoxygenation and respiratory acidosis are the most significant side effects in sedation. These effects are particularly frequent when two or more types of drugs are administered in combination (Bhananker et al., 2006). By providing additional oxygen flow to the patient, for example using a nasal cannula or a non-rebreathing face mask, sufficient oxygen supply is often ensured. However, proper oxygen supply does not mean sufficient breathing when in an unsteady state and when breathing an oxygen-enriched gas mixture.

  US Pat. No. 5,806,513 (Tham et al) provides a control that allows a closed circuit anesthesia delivery system to maintain a user defined oxygen and anesthetic concentration using a flow minimization routine. A system is disclosed.

US Pat. No. 7,034,692 (Hickle) discloses a system for monitoring a patient's oxygen supply status and preventing false alarms, annoying alarms or over-reaction alarms while performing a medical procedure. is doing. The monitoring data is processed by a sensitive alarm algorithm and a highly specific alarm algorithm. These algorithms generate silence conditions, quasi-obvious alarm conditions or explicit alarm conditions, and / or enable the most careful state in the system. The system provides an automatic response to a sensitive, highly specific alarm algorithm and reduces alarm false positives / alarm false negatives in a way that is not noticed by the user.

  PCT patent WO 2005/082369 (Shafer et al) discloses an opioid formulation for intrapulmonary administration during pain treatment. This formulation is dispensed by a pulmonary drug delivery device. This device may require deliberate patient effort for operation. The formulation comprises a biocompatible carrier that delays the release of the drug on the lung surface, such as at least one rapidly developing opioid and at least one long-acting opioid (e.g., liposome-encapsulated opioid). Containing opioids). This formulation uses the side effects of opioids that are rapidly expressed and encapsulated by liposomes to allow patient self-control of drug intake.

3. References

SUMMARY OF THE INVENTION A wide variety of drugs are used in modern anesthesia practice. The most common general anesthetics are barbiturates, benzodiazepines, ketamine and propofol. On the other hand, opioids represent the most relevant analgesics. In the clinical situation, anesthetics and analgesics are delivered by intravenous injection, intramuscular injection, rectally or by inhalation (in the case of volatile medicinal products). The pharmacological effect of the administered drug depends on, among other factors, the dosage, dosage profile and patient sensitivity.

  In the 1950s, Bickford (US Pat. No. 2,690,178) and Bellville (US Pat. No. 2,888,922) developed a new dosing paradigm and dosing procedure in anesthesia health care. As the sophistication of monitoring systems and understanding of physical function progressed, their early work followed several other contributions to improving drug delivery. For example, Zbinden and Westensko have proposed an innovative method for managing drug administration based on sophisticated control algorithms (eg Westensko et al., 1986 and other publications).

  Currently, among the anesthesiologists, the following dosing methods are adopted: manual bolus administration and / or continuous infusion, target-controlled infusion (TCI), patient self-regulating sedation (PCS) . Manual medication performed by a clinical caregiver exposes a few drawbacks, including the need for the caregiver to select a drug dose based on the estimated blood concentration. Conversely, when using TCI, the goal to be achieved by the anesthesiologist is the prediction of plasma or effect site concentration rather than the choice of infusion rate. The device controls drug delivery based on a built-in pharmacokinetic model of a specific drug. TCI is not responsible for two potential sources of error: discrepancy between predicted and actual concentrations, pharmacological variability between individuals and within individuals. The former cannot be measured or corrected during surgery. The latter can be compensated for by adjusting the targeted concentration for the desired and / or undesired effects observed in the patient. That is, an appropriate target concentration can only be established after a temporary underdose and / or overdose. PCS devices, on the other hand, can only be used by collaborative and well-educated patients. These designs cause fluctuations in sedation and anesthesia levels. PCS is considered a safe dosing method because unresponsive patients cannot operate the device. As a result, administration of the drug stops. However, the time lag between medication delivery and maximum drug effect causes unintentional overdose by the patient himself.

  US Pat. No. 6,745,764 (Hickle) discloses a drug delivery system with an integrated patient interface. The patient operates this interface to transmit a medication change request to the drug delivery device. The system can determine patient responsiveness by estimating the patient's spontaneous response to stimuli (eg, auditory or vibration indication). The system manages drug delivery in response to patient interface requirements and patient response data.

  In recent years, many attempts have been made to improve anesthesia health care. Here, some important achievements in the design of dosing treatment are summarized below.

  European Patent 1,547,631 (Barvais et al) discloses a system utilizing a computer. This system increases the safety of intravenous drug delivery and enables the transfer of expertise to inexperienced caregivers.

  US Pat. No. 6,807,965 (Hickle) discloses a system for conservatively managing drug delivery according to a safety data set stored in a memory device. The data set reflects both safe and unfavorable physiological parameters and predefines a normal range. This system monitors the patient's physiological status (including unconscious depth in the patient). It compares the signal supplied by the patient monitoring device with the stored safety data set and responds with conservative controls (ie, reduction, limitation or interruption) in drug delivery.

  PCT patent WO2001 / 083007 (Struys et al) discloses a system and method for performing drug administration based on patient response profiles. A patient's individual response profile is identified by a least squares algorithm. Following this approach, the difference between the sensed patient characteristics and the estimated curve is minimized, thereby obtaining an optimally fitted pharmacological Hill curve.

  The use of individual Hill curves in adjusting drug delivery overcomes large pharmacological variability between patients. In one embodiment of the invention, the system uses a patient's electroencephalogram (EEG) signal or bispectral index (BIS), thereby assessing the response profile of sedation depth in the patient. .

  PCT Patent Publication No. 2005/072792 (Struys et al) discloses a management system that manages drug delivery according to a patient's specific response profile. This system uses the bispectral index and other EEG measurements with the necessary processing (such as center frequency, spectral edge, and entropy rating index) to determine the patient response profile. The system applies techniques from Bayesian statistics, thereby adapting response profile parameters to changes that occur in patient response to medication.

Problems in sedation are constituted by the lack of MAC and an artificial tolerant respiratory monitor for use during conscious sedation. Possible methods for monitoring patient breathing in a clinical setting include chest appearance examination, detection of changes in chest electrical impedance, chest gage strain gauge measurement, ECG detection of respiratory rate (eg, respiratory sinus Arrhythmia (RSA) detection, cardiac cycle autoregressive spectrum analysis, heart electrical axis fluctuations, etc., nasal thermistor, plethysmography, spirometry or airway pressure monitoring, end-tidal CO ₂ partial pressure (PetCO ₂ ) Capnographic evaluation. Nonetheless, none of the methods has proven to be completely sufficient for use during sedation. For example, measurement of respiratory flow (or minute ventilation) by visual inspection is not practical or reliable. In the absence of other useful breath measurements, it represents a method that anesthesiologists trust to verify whether a patient has become apnea. It is clear that it works very poorly with respect to reliability, accuracy, reproducibility and automation. On the other hand, measuring a change in chest impedance can evaluate a tidal volume. However, this method tends to be artificial. Patient and cable movement reduces the SNR of the detected signal. Thus, the measurement of respiratory rate caused by changes in chest impedance is not appropriate for use during surgery. Capnography is the most reliable method in respiratory monitors, but instead suffers from falsely low readings, especially when upper airway obstruction occurs. This capnographic device uses a nasal cannula for sampling exhalation. The cannula is 3-5 cm long and does not impair spontaneous breathing. However, it makes measurements inaccurate when the patient breathes through the mouth. Other sampling configurations use a facial mask. The tube and mask dead space itself reduces the reliability of the PetCO ₂ measurement. Therefore, only respiratory rate data is usually considered.
Both configurations are sensitive to superficial breathing and airway obstruction. In conclusion, none of the ventilation methods described so far meet the requirement for full use in clinical situations.

Patient relevance can be determined indirectly by measuring transcutaneous CO ₂ pressure (PtcCO ₂ ) and oxygen saturation (SpO ₂ ) (Akio et al., 2004). ). For this purpose, innovative devices that combine a percutaneous CO ₂ sensing and pulse oximeter, recently entered the market. Currently, monitors as described below are commercially available. These monitors are: SenTEC AG (Therville, Switzerland) V-Sign® sensor, Radiometer A / S (Copenhagen, Denmark) TCM4, TCM40, TOSCA500 and MicroGas 7650. These devices use sensors placed on the earlobe to continuously measure the patient's heart rate, SpO ₂ and PtcCO ₂ . Steady state bias and reaction rates are sufficient. Thus, these sensors provide a fast and reliable breathing guide suitable for use during MAC and conscious sedation.

  PCT patent WO2002 / 041770 (Tschupp et al) provides a sensor for measuring physiological parameters (such as oxygen and carbon dioxide) in blood. The sensor includes a measuring device and a digital sensor signal processing device, and outputs a digital output signal.

PCT patent WO 2005/110221 (Gisiger et al) discloses a process for measuring transcutaneous CO ₂ partial pressure in the earlobe with a sensor device. This process uses a transcutaneous CO ₂ partial pressure measurement device and a heating system that heats the contact surface of the sensor.

In addition to the evaluation of a sufficient patient monitor, PtcCO ₂ signal acts as a surrogate endpoint regarding drug administration. The fundamental concept here comes from the medication protocol used to treat cancer. Drug administration in oncology is periodically limited by the occurrence of side effects, rather than obtaining optimal therapeutic effects. This dosing paradigm is called “maximum systemic tolerance (MTSE)”. The application of the MTSE paradigm to MAC and conscious sedation means providing analgesia and anxiety (desired effects) by controlling drug delivery based on respiratory inhibition (adverse effects). In order to obtain optimal analgesia or sedation treatment, it is usually not necessary to produce maximal respiratory depression (ie systemic exposure). On the contrary, treatment is determined by the optimal amount of respiratory depression tailored to the individual. Later on, we will refer to this concept as IOSE (Personal Optimal Systemic Exposure).

IOSE has a clear clinical evaluation when the following conditions are met:
(A) Simple and robust measurement of the desired effect is useless.
(B) Concentration versus effect curves for desirable and undesired effects are related to each other.
About (a) ... The desired effects (analgesic, anti-anxiety and / or sedation) in MAC and conscious sedation can be easily measured whether awake or sleepy. Spontaneous dissatisfaction, movement, VAS scale and OASS scale give clear information as to whether the desired effect has been achieved. Nevertheless, these measurements can only be detected after stimulation. Undesirable patient responses often cause overcorrection by anesthesiologists that also cause side effects. EEG
Guidance based on also means that it is possible to give a continuous measure of the desired effect. For example, the Aspect Medical System's Bispectral Index (BIS®) is an EEG-derived parameter that evaluates hypnotic components in anesthesia independent of patient stimulation. However, EEG swings greatly for moderately sedated patients and is not sensitive to opioids within the treatment area. In conclusion, none of the methods can be used in the MAC to assess the desired effect.
About (b) ... For mu-agonist opioids and GABAergic drugs (such as benzodiazepines and propofol), the strength of respiratory inhibition is equivalent to the strength of analgesia and sedation. This effect is explained by the interaction between the drug and the neuroreceptor. Mu receptors in the brainstem and thalamus mediate both the highly effective opioid analgesic and respiratory function-suppressing effects. Benzodiazepines and propofol exert their sedative / sleep action at GABA receptors, an action that has also been shown to cause respiration inhibition. For this reason, these drugs always cause respiratory function suppression, which is always correlated with analgosedation (or vice versa). According to the idea that a drug that binds to a specific receptor type causes both analgesia / sedation and respiratory depression, it is always possible to increase both the analgesic / sedation and respiratory function by increasing the drug concentration. Both will increase. It is possible to “tune” the analgesia / sedation for respiratory depression, and selecting the maximum degree of anti-respiratory depression will result in the maximum acceptable concentration at which the analgesic / sedative action can be extinguished quickly . For example, based on the PCO _2, dosing can be a fit individuals, This results in IOSE. Analgesia can only be evaluated after an unpleasant stimulus is applied. The proposed new medication paradigm allows physicians to use the most objective measure of opioid action (respiratory depression) in the therapeutic area to obtain analgesic concentrations and to administer medication individually Can be

Under certain conditions (spontaneous breathing, lung pathology is not too bad), the IOSE concept can also be applied to an intensive care unit (ICU). In this configuration, conscious sedation is performed primarily to provide post-surgical / post-traumatic analgesia and the ability to withstand the endotracheal tube. All conventional methods of controlling sedation in the ICU are suboptimal. For example, measuring electrical CNS activity using BIS® monitoring is not reliable when sedation levels are light. Moreover, a sedation score cannot be obtained continuously. Nevertheless, the transition from controlled ventilation to auxiliary ventilation is a well-established trend in ICU practice. This shift, as an alternative indicator of sufficient calming, proposes a possibility of using minute ventilation and / or respiratory gas measurement (e.g. PCO _2). Indeed, excessive sedation, to cause a decrease and an increase in PCO ₂ minute ventilation, and in under-sedation, opposite happens. For this reason, IOSE can be considered an appropriate medication paradigm for intensive care analgosedation.

In the clinical situation, anesthesiologists apply the IOSE concept to the observed undesirable effects by titrating drug delivery. This is because the measured evaluation item is associated with the therapeutic effect. For example, by targeting PCO ₂ of 50, 55 or 60 mmHg, it is possible caregiver to manage drug administration. The difference between the PCO ₂ target and a non-sedation value of about 40 mm Hg is a major cause of the desired range of pharmacological effects. Furthermore, the IOSE paradigm can be embodied in an automated dosing device as disclosed by the present invention.

The said system disclosed here provides the structure which controls administration of the analgesic which has the side effect which suppresses a respiratory function, a sedative, and / or a sleeping pill. Drug delivery occurs in spontaneously breathing patients under consciousness suppression caused by the drug. The drug delivery control device focuses on the physiological situation being monitored to determine a medication profile that ensures sufficient and safe sedation with minimal side effects. Respiratory failure, blood deoxygenation and hypercapnic acidosis are the most serious adverse effects caused by drugs. The controller manages drug delivery based on feedback information provided by one or more patient monitoring devices. This feedback data reflects the patient's respiratory status, including respiratory acidosis and respiratory gas content.

  As understood in the field of automatic control, in the foregoing and following description we refer to a feedback loop control system. In engineering and mathematics, control theory deals with dynamic system behavior. A system in which a change is occurring or a functioning function is characterized by inputs and outputs. Feedback is the process by which some ratio, or more generally a function of the output signal in the system, is transferred (feedback) to the input signal. This is often done intentionally to control dynamic behavior in the system. Continuous feedback in the system creates a feedback loop.

  In all feedback loops, information about the result of the change or action is sent back to the system input in the form of input data. Feedback results in different adjustments depending on the difference between the actual input and the desired input. A feedback loop control system usually includes a sensor of a control variable, a reference input or set value that specifies a value that the control variable should have, and a comparator that compares the actually detected value or feedback signal with the set value or reference input. Contains. The output of the comparator is usually called an error signal. The polarity of the error signal determines the direction in which the correction needs to be made. The feedback loop control system further includes a control mechanism or controller that is activated by an error signal to manipulate the input of the system using an actuator, thereby obtaining the desired effect on the output of the system.

  Several types of controllers or control mechanisms have been proposed. These differ in their specific decision-making principles. A simple type of controller is a proportional controller. When using this type of controller, the output of the controller (ie, the controller action) is proportional to the error signal. Proportional control is characterized by a very low degree of complexity, but has drawbacks. That is, the most important point is that, for most systems, it cannot completely eliminate errors or deviations from the desired value (set value) in the measured value. Alternatives to proportional control include proportional-integral (PI) control and proportional-integral-derivative (PID) control. These controllers are capable of adjusting the process output based on the error signal history (integration action) and rate of change (differentiation action), thereby increasing the accuracy and stability of the control. . A more complex type of control is model predictive control (MPC). The MPC controller utilizes an empirical model in a dynamic system, thereby predicting future behavior in this independent variable based on known values in the independent variable. MPC improves on simpler types of control by predicting how the system reacts to input, ie, the effects produced by a previously known input. Feedback information is used to correct model inaccuracies because mathematical models often cannot fully describe system behavior. Another advantageous type of control is fuzzy logic control. In fuzzy logic control, the truth of any description is a matter of degree. Fuzzy logic uses mapping input space to output space by using a set of rules (eg, a list of “if-then” descriptions). The interpretation of the “if-then” rule includes two steps. That is, evaluate the precedent and apply the result to the necessary result. Thus, a fuzzy logic controller is a controller that interprets input values and assigns values to outputs based on a set of rules.

  As mentioned above, the error signal gives the system information about the magnitude and direction of adjustments made by the control mechanism at the input. This means that the feedback loop control mechanism manipulates the input (or vice versa) to decrease the output if the output exceeds a set value. As a result, the system can be stabilized as a whole, and even in the case where disturbance occurs, an equilibrium in the vicinity of a desired set value can be maintained. Applying this approach to the drug administration paradigm means that the drug administration is adjusted according to the situation detected in the patient. If the pharmacological effect is too strong, drug delivery is reduced. Also, if the effect is too weak, it is increased. This can be understood as titration of drug delivery tailored to the effect. Generally speaking, the scope of the feedback controller is consequently well beyond the range of alarm systems or safety systems that detect dangerous situations in patients and reduce or stop medication administration.

  Unlike a feedback controller, an open loop controller is a type of controller that uses only the current state and / or model of the system to compute the input to the system. An open loop controller (also called a non-feedback controller) does not use feedback to determine whether its input has reached a set point. This means that the system does not observe the output of the process during control. Thus, a pure open loop system cannot compensate for system disturbances. The principles of open loop control have been applied several times in the case of anesthesia (eg TCI (target controlled injection) technology). One embodiment of the invention disclosed herein utilizes non-feedback control.

Constant vigilance, no fatigue, predictable and reproducible behavior are general characteristics of the machine, which fully justify the design of the device for automatic drug delivery To do. These properties are of particular value in dynamic situations such as anesthetic delivery where revocation or delay can lead to the worst consequences. In addition, the feedback device can respond well to the occurrence of painful stimuli and other surgical disturbances by detecting changes in the measured endpoint. For example, pain causes respiratory changes along with other autonomous responses. Some studies have reported that pain perception generally has a stimulating effect on respiration (eg, Sarton et al., 1997; Glynn et al., 1981). Such an effect is exerted through the following physiological mechanisms.
・ Pain activates the metabolic action of carbon dioxide. In other words, following the painful stimulus, speed of CO ₂ generated in the body is increased. Indeed, pain causes the release of catecholamines, which subsequently activate cardiac and respiratory activity. The extended physiological function determines to increase both O ₂ consumption and CO ₂ production.
• Pain reduces the physiological PCO ₂ setting in arterial blood (Glynn et al., 1981).
The pain effect is a tonic drive that increases minute ventilation independent of chemoreceptors. That is, the respiratory response to pain is not mediated by central chemoreceptors in the medulla and peripheral chemoreceptors in the carotid body, but rather intensively through the respiratory nerves in the brainstem (Sarton et al., 1997).
Painful stimuli do not affect the slope of the CO ₂ response curve (curve representing minute ventilation versus PCO ₂ at different PO ₂ ).
Physiological mechanisms as described above cause an increase in overall minute ventilation following painful stimuli. The effect on respiration reaches steady state in about 3 minutes and can be quantified as a 20% increase in minute ventilation, followed by a decrease in carbon dioxide levels.

  Thus, painful stimuli cause changes in respiratory status. This change can be detected by the patient monitoring device and can be corrected by a feedback design in the proposed system. Other surgical disturbances that affect the patient's breathing can be similarly suppressed by this system.

  In addition, information on pharmacokinetic / pharmacology (PK / PD) and respiratory and cardiovascular regulation dynamics can be incorporated into our proposed system and method. Conversely, caregivers need to learn about the behavior of physiological systems in unsteady states and must deal with variations between individuals.

  Finally, automatic devices can be supplemented by safety devices. For example, in order to limit drug administration within a safe range, a minimum value of oxygen saturation in arterial blood can be defined in advance. Other possible safety parameters are the predicted drug concentration in the working compartment or blood, the overall dosage given to the patient, and the dosage rate. The safety device can perform an immediate stop of drug delivery while maintaining the current drug concentration / dose rate.

Regardless of the specific settings, medications and endpoints, conscious sedation (frequently) and MAC (sometimes) are performed by a caregiver who is not specially trained to administer anesthetics, such as a nurse. These caregivers are not used to the complexity of human respiratory control. Indeed, minute ventilation is regulated by a number of intrinsic and extrinsic factors, including physical / sensory stimulation levels, drug concentrations, O ₂ partial pressure and CO ₂ partial pressure. Each factor has a different effect on respiration, both in terms of response magnitude and dynamics. Thus, untrained caregivers tend to over- and under-dose on patients compared to anesthesiologists. In the case of overdose, they are also not familiar with the means of resuscitation. On the other hand, it is often impossible to strain an anesthesiologist trained in conscious sedation due to cost and lack of manpower. The delivery of so-called “safe” drugs (poor opioids such as meperidine and midazolam) limits the clinical impact because this frequently results in insufficient light sedation.

  In conclusion, the problems of sedation and analgesia have not yet been solved. There is a clear clinical need to simplify drug administration, increase patient safety and comfort, and reduce clinical costs. The invention presented and disclosed herein is intended to solve these problems and proposes a practical, effective and safe solution. The system and method according to the present invention allow caregivers to perform analgo sedation within safety limits and prevent overdosing and underdosing. Other focal points in the present invention are described below.

  A system for controlling the administration of a respiratory function inhibitor or a mixture of drugs to a patient breathing spontaneously comprises an indexed automatic titration for the respiratory function inhibitor or a mixture of such drugs to the patient or A drug delivery unit suitable for continuous automatic titration, and a control device for receiving a measurement signal related to the respiratory state of the patient and outputting a control signal to the drug delivery unit, the control device comprising: By maintaining the measurement signal associated with a respiratory condition in a predetermined state, the patient is configured to provide sufficient sedation and / or analgesia.

The present invention provides an apparatus and associated method for delivering one or more anesthetics and analgesics to a spontaneously breathing patient. The present invention is intended to alleviate pain, discomfort and / or anxiety associated with medical or surgical treatment by administering a sufficient and safe sedative. The present invention is also intended to optimize drug administration to prevent underdosing and / or overdosing to patients and to minimize the risks associated with respiratory anesthetics. The system is suitable for use during medical or surgical treatment where it is desirable or necessary to eliminate patient pain, discomfort and / or anxiety due to patient sedation .

  A management system according to the present invention includes one or more patient monitoring devices for monitoring at least one physiological condition reflecting a respiratory condition in the patient, and a drug delivery system for supplying one or more drugs. And a control device for driving the distribution system.

  The patient monitoring device outputs one or more signals for detection, measurement, or estimation regarding at least one physiological condition affecting the respiratory condition in the patient. A drug delivery system supplies one or more drugs or a mixture of drugs to the patient. The control device drives the drug delivery system. In one form of the invention, the controller interconnects the patient monitor device and the drug delivery system.

  This configuration has the purpose of controlling the administration of analgesics, sedatives and / or hypnotics with side effects that inhibit respiratory function to spontaneously breathing patients under consciousness suppression caused by drugs. ing. The drug delivery control device directs attention to the patient's physiological situation that reflects the respiratory condition, including the respiratory gas content in the patient's body, being monitored and / or estimated. As a result, an optimal dosing profile is determined and drug delivery within an effective and safe range is ensured.

  To achieve the foregoing and other objectives, the treatments described herein for managing patient pain and / or anxiety control the delivery of anesthetics based on predicted internal drug concentrations. Is included. For example, drug administration can be based on the working compartment or the predicted drug concentration in the blood. Predicting anesthetic concentrations is obtained by pharmacokinetic modeling and can also take into account demographic covariates (eg, age, gender, weight, height and others) in the patient.

In another aspect of the invention, the method takes into account the expected pharmacological side effects in order to determine the dosing profile. Side effects are estimated from the behavior of the respiratory model built in the control system. For respiratory function inhibitors such as opioids and propofol, respiratory failure is the most obvious undesirable effect. In one embodiment, the method is based on respiratory guidelines such as respiratory rate (eg, for an intubated patient), minute ventilation (eg, for an intubated patient), tidal volume, etc. , Control drug delivery. This extension of the method utilizes the predicted content of respiratory gases in the body as an indirect assessment of respiratory inhibition. Parameters reflecting the oxygen and carbon dioxide content in the body (eg, O ₂ saturation and CO ₂ partial pressure (or pressure)) are used to determine the dosing profile. In a preferred embodiment, the controller utilizes the predicted transcutaneous PCO ₂ value.

In accordance with one aspect of the invention, the medication profile is determined based on a feedback signal provided by the patient monitoring device. The feedback signal reflects one or more physiological conditions that allow monitoring of the respiratory condition and that are corrected in the presence of anesthesia. In one embodiment of the invention, the monitoring device outputs information relating to the patient's breathing and / or respiratory acidosis and / or information relating to the content of respiratory gas in the body after administration of the respiratory function inhibitor. In a preferred embodiment, the drug delivery controller receives data from a combined pulse oximeter / transcutaneous PCO ₂ sensor.

  In another aspect of the invention, the method utilizes information specific to the feedback signal to improve drug delivery safety. The controller continually redetermines the dosing profile based on the measured respiratory guidelines with the combined objective of obtaining the necessary therapeutic effect and preventing drug overdose. If respiratory drive dysfunction becomes apparent, the system limits or interrupts drug delivery to minimize patient risk.

  In yet another aspect of the invention, the feedback signal provided by the monitoring device is used to adjust the behavior of the basic respiratory model to the patient's responsiveness. If the signal is lost and / or if the sensor fails, fails or breaks, the control system can switch from closed loop operation to open loop operation, with effective pain and / or effective drug delivery. Or you can continue to provide anxiety management.

  The advantage of the method described here is that the drug administration can be tailored to the patient's specific needs, depending on the level of stimulation, the desired analgesic and anxiolytic effects, and individual sensitivity to the drug. There is something you can do. Regardless of the clinical situation, drug and endpoint, this method ensures patient safety and comfort, minimizes the risk of drug under- and over-dose, and reduces clinical costs.

  Further features and advantages of the present invention, as well as the structure and operation of various embodiments of the present invention, are described below.

1 is a conceptual illustration of a system according to an embodiment of the present invention. 1 is a graph of effects and side effects versus drug concentration for opioid remifentanil. 1 is a graph of effects and side effects versus drug concentration for opioid alfentanil. Figure 2 is a graph of effects and side effects versus drug concentration for propofol.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The embodiments described herein are not intended to be exhaustive and are not intended to limit the invention to the precise form shown. This embodiment was chosen to illustrate the principles of the invention and its application.

FIG. 1 shows a preferred basic structure in a device according to an embodiment of the present invention. This device supplies an analgesic, sedative and / or hypnotic with side effects that suppress respiratory function to a patient 1 who is breathing spontaneously who is undergoing a medical or surgical procedure Is. Block 1 is referred to as a patient and represents the patient, but has at least one sensor 7. This sensor 7 outputs an output signal 24 which is a sensory signal related to the respiratory state of the patient. Of course, more than one sensor can be provided, and these sensors can also output signals relating to different indicators of the respiratory condition. Of course, patient 1 does not have an input signal itself. However, FIG. 1 shows that the device includes a drug delivery unit 3. The drug delivery unit 3 has an index-linked output or a continuous output as an output for an analgesic, sedative and / or hypnotic supplied to a patient via a drug delivery means 22 (for example, an infusion tube). It is. In addition, an electrical indication for the actual output of the analgesic, sedative and / or sleeping pill from the drug delivery unit 3 is sent via 23 to the processing unit 2 (inside the control device 6) as an entry signal. Communicated. This processing unit 2 corresponds to a database and computer software product in the processing unit relating to the patient model. The patient monitoring device 4 measures the respiratory state of the patient 1 via input signals provided by one or more sensors 7. The model prediction calculator 5 (inside the control device 6) estimates the respiratory state from the patient model 2 received via the electrical display 25 and the control unit 8. The control unit 8 outputs electrical drug information 27 to the device distribution unit 3 for index-linked titration or continuous titration. The drug delivery is a direct patient measurement 20 (closed loop mode, one of the preferred embodiments) or model prediction 26 (open loop mode, one of the preferred embodiments, in particular, sensor signal and target controlled injection modes. According to the respiratory condition). The titration by the control unit 8 includes a control mechanism that is executed in the processing unit using a decision making principle such as PID (proportional / integral / derivative) implemented in software. This titration is guided by an error signal which is calculated by comparing the set value with the patient measurement 20 or the model prediction 26. The decision making principle of the control mechanism in this embodiment is not limited to PID, but may be based on other appropriate principles. During closed-loop operation, patient model 2 is adapted and updated to a continuous or exponentially shaped shape via 21 based on actual patient measurements 20.

  In a preferred embodiment, the control unit 8 comprises a display 9 and one or more input / output systems 12 for user interaction. The preferred embodiment further comprises a drug database 10. This drug database 10 contains pharmacokinetic and pharmacological properties of the drug or mixture of drugs administered to the patient, these characteristics being in particular the patient model in the control unit 8 and the control device 6. 2 can be adjusted in advance. The pharmacological data includes not only properties related to therapeutic effects, but also data on side effects (especially those related to the effects on the dynamics of respiration and cardiovascular regulation). In this preferred embodiment, such data from the drug database 10 is read into the controller 6 for later use.

  In a preferred embodiment, the control device 6 is supplemented by additional safety measures. This safety measure includes the following (a) to (c). (A) Minimum value of permissible oxygen saturation in arterial blood, as a “severe” safety measure, in which drug administration is immediately discontinued if exceeded. (B) The maximum and minimum predicted drug concentration in the working compartment that can be preset by the user as a “gentle” safety measure (if this concentration is reached, the concentration is maintained at this point and the operation is The user is notified of the open loop mode). (C) Infusion rate limit (for infusion drugs), overall drug dose for drug administration, and lockout time. In a preferred embodiment, all safety information and safety constraints are stored in a safety database 11 attached to the control device 6.

  In a preferred embodiment, the patient's respiratory condition is diagnosed by assessment of respiratory acidosis. This respiratory acidosis is preferably measured by measuring the amount of carbon dioxide contained in the blood. Alternatively, in another preferred embodiment, it is measured by measuring the amount of pH in the blood. This can be done in a variety of ways, and by obtaining information as described above, a display relating to the patient's respiratory condition is output.

  In a preferred embodiment, the carbon dioxide content in the patient's blood is measured by fast transcutaneous carbon dioxide partial pressure measurements. In other embodiments, the content of carbon dioxide in the patient's blood is measured by end-of-breath measurement of carbon dioxide. All such measurement systems are preferably complemented by independent sensors relating to the respiratory rate in order to detect single fault conditions in the sensory system.

  Preferred drugs for analgesia are opioids, especially alfentanil, fentanyl, remifentanil and sufentanil.

  Mixtures of respiratory function inhibitors and non-respiratory function-suppressing analgesics or non-respiratory function-suppressing sedatives are preferred for patients with atypical respiratory function-suppressing drugs and / or carbon dioxide hypersensitive patients. In a preferred embodiment, the non-respiratory function inhibitor is ketamine.

FIG. 2 shows a graph of effect and side effects versus drug concentration for the preferred use of opioid remifentanil for analgesia. Remifentanil has been used since the mid-1990s in most cases for intraoperative analgesia and conscious sedation. Useful data show its analgesic and respiratory function-suppressing efficacy (target concentration and completeness targeted by individual use of patient-controlled analgesia (Schragag et al., 1998; Cortinez et al., 2005)) The concentration, along with PaCO ₂ measured for the capture of respiratory depression, has resulted in a curve based on numerous observations on individuals regarding respiratory depression (Bouillon et al., 2003)). The graph shown in FIG. 2 shows (a) a specific maximum effect percentage as shown below on the left ordinate, and (b) a partial CO ₂ by [mmHg] on the right ordinate. Pressure (c) has a concentration of remifentanil in [ng / ml] on the side table. The explanatory text (legend) for the data trace of the graph in FIG. 2 is as follows. (1) On the left ordinate: analgesia measured as a percentage in patients with sufficient pain relief (visual analog scale <3.0, 0 indicates no pain, 10 is the worst pain imaginable ). A C50 of 2.8 ng / ml (concentration required to obtain half of the effect) has been reported and slope extrapolated. Data were obtained during extracorporeal shock wave kidney stone fragmentation (ESWL) in submerged fracture. (2) Similarly on the left ordinate: Respiration suppression measured as the rate of decrease in minute ventilation when the PCO ₂ is not controlled (clinical situation; the accompanying high carbon dioxide gas is partially Neutralizing the effect of opioids on hourly ventilation). (3) Fixed value expressed as a vertical line on the horizontal axis: C50 for respiratory depression, i.e. the concentration of remifentanil at the effect site resulting in a 50% reduction in the minute ventilation of iso-high carbon dioxide. Note that this value can be used to predict both analgesia and minute ventilation when PCO ₂ is not controlled. For example, a C50 of 1 for respiratory depression provides sufficient relief (pain after surgery, abdominal surgery) while suppressing rest ventilation. (4) Fixed value expressed as a vertical line on the horizontal axis: measured in cardiac and orthopedic patients operating patient-controlled analgesia devices to sufficiently relieve post-surgical pain Medium concentration. (5) On the right ordinate: PCO ₂ expressed as an absolute value in mmHg.

FIG. 3 shows a graph of effect and side effects versus drug concentration for the preferred use of opioid alfentanil for analgesia. Alfentanil has been used since the late 1980s for analgesia during and after surgery. Useful data indicate its analgesic efficacy and respiratory function suppression efficacy. Target concentration targeted by individual use of patient-controlled analgesia (van den Nieuwenhuyzen et al., 1997; Schragag et al., 1999) and the effect of full concentration based on multiple observations on individuals with respiratory depression Curves have been obtained with PaCO ₂ that captures respiratory depression (Bouillon et al., 1999). The graph shown in FIG. 3 shows (a) a specific maximum effect percentage as shown below on the left ordinate, and (b) a partial CO ₂ by [mmHg] on the right ordinate. Pressure (c) has a concentration of alfentanil in [ng / ml] on the side table. The explanatory text for the data trace of the graph in FIG. 3 is as follows. (1) On the left ordinate: analgesia measured as a percentage of patients with sufficient pain relief (visual analog scale <3.0, 0 indicates no pain, 10 is the worst pain imaginable ). A C50 of 52 ng / ml has been reported and is extrapolated with a slope. This is based on the case of general surgery, gynecological surgery and orthopedic surgery. (2) Similarly on the left ordinate: Respiration suppression measured as the rate of decrease in minute ventilation when the PCO ₂ is not controlled (clinical situation; the accompanying high carbon dioxide gas is partially Neutralizing the effect of opioids on hourly ventilation). (3) Fixed value expressed as a vertical line on the horizontal axis: C50 for respiratory depression, i.e. the concentration of alfentanil at the effect site resulting in a 50% reduction in the minute ventilation of iso-high carbon dioxide. Note that this value can be used to predict both analgesia and minute ventilation when PCO ₂ is not controlled. For example, a C50 of 1 for respiratory depression provides sufficient relief (pain after surgery, abdominal surgery) while suppressing rest ventilation. (4) Fixed value expressed as a vertical line on the horizontal axis: moderate concentration measured in post-cardiac surgery patients operating patient-controlled analgesia devices to sufficiently relieve pain. A fixed value expressed as a vertical line on the horizontal axis. (5) On the right ordinate: PCO ₂ expressed as an absolute value in mmHg.

FIG. 4 shows a graph of effect and side effects versus drug concentration for the preferred use of propofol for analgesia. Propofol has been used since the late 1980s to provide conscious sedation and anesthesia. Useful data include its sedative efficacy (eg, suppression of bispectral index, parameters derived from EEG (Bouillon et al., 2004, “Pharmacodynamic interaction... (Pharmacological interaction)”)) and respiratory function Inhibition efficacy (Bouillon et al., 2004, “Mixed-effects modeling”) (mixed effects modeling) ”For these endpoints, a complete concentration effect curve shows PaCO ₂ to capture respiratory depression. The graph shown in Figure 4 shows (a) the percentage of the specific maximum effect as shown below on the left ordinate, and (b) [mmHg] on the right ordinate. partial CO ₂ pressure due to (c) Lateral table, [ng / ml] The explanatory text for the data trace of the graph in Figure 4 is as follows: (1) On the left ordinate: decrease in bispectral index (BIS: registered trademark) Hypnosis measured as: a surrogate endpoint for hypnosis / sedation derived from EEG, where 50 corresponds to surgical anesthesia and 60-75 is sufficient for conscious sedation. (2) Also on the left ordinate: PCO Respiratory depression measured as the rate of decrease in minute ventilation when not controlling ₂ (clinical status; the accompanying high carbon dioxide gas partially neutralizes the effect of propofol on minute ventilation (3) Fixed value expressed as a vertical line on the horizontal axis: C50 for respiratory depression, ie 50% of the minute ventilation of iso-high carbon dioxide The concentration of propofol in the effect-site resulting in small. Note that this value, it when not controlling the PCO _2, can be used to predict both the analgesic amount and minute ventilation For example, a C50 of 1 for respiratory depression provides sufficient sedation while hardly suppressing rest ventilation (4) On the right ordinate: PCO ₂ expressed as an absolute value in mmHg.

According to FIGS. 2-4, and taking into account the additional statistical variance, the carbon dioxide level setting (the partial pressure of carbon dioxide) for the therapeutic effect in the preferred embodiment is in the range of 35-80 mmHg, Preferably it is the range of 45-65 mmHg, and becomes the range of 48-55 mmHg ideally. Values in these ranges are particularly useful for transcutaneous acquisition of carbon dioxide levels. However, it is also possible to measure CO ₂ directly as a gas near the patient's lungs, even within the patient's intubation. The value to be selected can be adjusted by the caregiver.

  For the case of moderate anesthesia, the preferred agent for moderate to high pain levels experienced from light to heavy surgery is a mixture of propofol and remifentanil. For the fastest recovery and maximum therapeutic effect, the dosage ratio of remifentanil to propofol is 0.0015: 1 to 0.0035: to maintain a fixed concentration range in plasma or at the site of effect. It is preferably selected from the range of 1. In the case of mild sedation, remifentanil for low to moderate pain levels that require additional relief of discomfort and / or anxiety experienced during minor surgery or diagnostic intervention A preferred ratio of to propofol ranges from 0.0002: 1 to 0.0008: 1.

  The controller is configured to keep the measurement signal associated with a respiratory condition in a predetermined state and thereby provide sufficient sedation and / or analgesia to the patient. This means that the database 10 or the user preferably selects a preset setting value (for example, carbon dioxide level) as described above. The condition can be a point given on the control curve, where the feedback control is controlled by a normal closed loop control system monitoring the system. Such closed loop control systems known from control theory can also use higher or lower level intervals, for example at the carbon dioxide level. Such a state is intended to be achieved using the controller 6 in connection with other elements (such as those shown in FIG. 1).

  In a preferred embodiment, the continuous system mode is implemented as a discrete time system or an exponentially linked system. These systems are related to the time constant of the underlying physiological system, but preferably use a lower time constant. For the drug and drug mixture and changes in the patient's respiratory condition caused by the drug, the preferred range of system time constants is 1 to 60 seconds. Thus, system update rates (eg, system internal status updates, drug delivery unit updates, patient monitor readouts) are similarly in the range of 1-60 seconds (eg, 5 second interval, 10 second interval, or 20 Preferably in seconds).

In a preferred embodiment in an open loop system, the model prediction is used for target controlled injection (TCI; injection method to reach a preset concentration as soon as possible without exceeding). This is because, according to FIG. 1, the patient monitoring device 4, and thus the measurement 20, is either (a) not used, or they are not included in one shape of this embodiment, or (b) they are , Which is used as an input value in other shapes of this embodiment. In the first form in this embodiment, the predicted level of respiratory depression, shown as fractional breathing in the reference breath, is used to limit the calculated infusion rate, thereby pre-determining A plasma concentration or effect site concentration is reached. In the second shape in this embodiment, the actual measurement (20) associated with the patient's respiratory condition is used by the respiratory model to calculate the fractional respiration. This data is then used to limit the infusion rate, thereby obtaining a predetermined plasma concentration or effect site concentration. Thus, in both configurations in this preferred embodiment, the maximum allowable decrease in fractional breathing is a factor in limiting the infusion rate in the TCI method and can be selected by the caregiver. In a preferred embodiment, the fractional respiration is in the range of 0.4 to 0.95, ideally in the range of 0.6 to 0.8. (A) in the pharmacokinetic model of respiratory function inhibitors for the TCI algorithm, (b) in combination with its pharmacological effects on respiration, and (c) carbon dioxide kinetics and kinetics in these embodiments In combination with a breathing model using, ensures that a preselected concentration is reached as soon as possible while maintaining breathing at a safe level.

DESCRIPTION OF SYMBOLS 1 Patient 2 Patient model processing apparatus 3 Drug delivery unit 4 Patient monitor device 5 Model prediction
6 Calculator control unit (dotted line box)
7 Sensor unit 8 Control unit 9 Display 10 Drug database 11 Safety database 12 Input / output system 20 Patient measurement 21 Patient model update 22 Drug delivery to patient (eg, infusion tube)
23 Electrical display in drug delivery 24 Sensory signal 25 Electrical model display 26 Electrical display in model prediction 27 Electrical drug information

Claims (16)

In a system for controlling the administration of a respiratory function inhibitor or a mixture of drugs to a patient breathing spontaneously,
A drug delivery unit (3) suitable for exponentially linked automatic titration or continuous automatic titration of respiratory function inhibitors or mixtures of such drugs for said patient (1);
A control device (6) for receiving a measurement signal (20) relating to the respiratory state of the patient (1) and outputting a control signal (27) to the drug delivery unit (3);
A system wherein the controller provides sufficient sedation and / or analgesia to the patient by maintaining the measurement signal associated with a respiratory condition in a predetermined state.   With the control device (6) limiting the drug administration rate to always ensure fractional breathing in the preferred range of 0.4-0.95 and the ideal range of 0.6-0.8, the said The system according to claim 1, wherein the plasma concentration or effect site concentration of the selectable drug is obtained as fast as possible via the drug delivery unit (3).   The system according to claim 1 or 2, wherein the measurement of the respiratory state is based on an evaluation of respiratory acidosis by measuring the content of carbon dioxide in blood.   4. A system according to claim 3, wherein the partial pressure of carbon dioxide in the situation is in the range 35-80 mmHg, preferably in the range 45-65 mmHg and ideally in the range 48-55 mmHg.   The system of claim 3, wherein the carbon dioxide measurement is an end-tidal partial pressure measurement.   The system of claim 3, wherein the carbon dioxide measurement is a transcutaneous partial pressure measurement.   The system according to claim 1 or 2, wherein the measurement of the respiratory state is based on an evaluation of respiratory acidosis by measuring pH in blood.   The system according to any one of the preceding claims, wherein the control device (6) comprises a pharmacokinetic and pharmacological model of the drug or mixture of drugs used by the delivery unit (3).   The controller (6) further comprises a model for the effects on the respiratory condition caused by the drug and a respiratory model including carbon dioxide kinetics and kinetics as a guide to the patient's respiratory acidosis. A system according to any one of the preceding claims.   System according to any one of the preceding claims, wherein the drug delivery unit (3) comprises an infusion pump and / or a syringe pump.   11. The continuous titration is of discrete time type and is based on the update rate of the system, in particular the update rate at time intervals ranging from 1 second to 60 seconds. System.   The drug or mixture of drugs delivered by the drug delivery unit (3) is an opioid or contains an opioid, in particular the opioid is remifentanil, alfentanil, sufentanil or fentanyl. The system according to claim 1.   13. System according to any one of the preceding claims, wherein the medicament or mixture of medicaments delivered by the medicament delivery unit (3) is propofol or contains propofol.   The drug mixture comprises at least one respiratory function inhibitor and an additional non-respiratory sedative or analgesic agent, in particular, the drug mixture comprises opioid and ketamine; The system according to claim 1. In a mixture of drugs containing remifentanil and propofol,
The ratio of these remifentanil to propofol is between 0.0015: 1 and 0.0035: 1 when used for anesthesia, or 0.0002: 1 and 0.002 when used for sedation. Is a ratio to obtain a steady state concentration ratio in plasma or effect site between 0008: 1,
15. A mixture of medicaments used in particular in connection with the system according to any one of claims 1-14. In a method of controlling the administration of a respiratory function inhibitor or a mixture of drugs to a patient breathing spontaneously,
Obtaining a measurement signal related to the respiratory state of the patient;
Outputting a control signal to a drug delivery unit suitable for exponentially linked automatic titration or continuous automatic titration for respiratory function inhibitors or a mixture of such drugs for the patient, and
The method wherein the controller provides sufficient sedation and / or analgesia to the patient by maintaining the measurement signal associated with a respiratory condition in a predetermined state.

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