Álvarez Nº 14.053, Chile

Propofol Sedation vs. Anaesthetist Guided Anaesthesia in Oocyte Pickup

Effects of Propofol on Brain Function in Patients With Parkinson's Disease

Performance Analysis of Hermetic Closed-loop Anesthesia Delivery System

Propofol total intravenous anaesthesia (TIVA) is a preferred technique for providing induction and maintenance of general anaesthesia (GA). As opposed to the conventional inhaled anesthetics for maintaining GA, propofol TIVA has several advantages, such as, lower incidence of postoperative nausea and vomiting (PONV), antinociceptive and anti-inflammatory action, anti-neoplastic activity, and most importantly, its environment disposition (no greenhouse effect); and therefore, has potential to replace inhaled vapors for GA. The introduction of target-controlled infusion (TCI) pumps has allowed precision control in propofol delivery as compared to the conventional manually operated infusion pumps. In manually operated infusion pumps the clinician regulates the propofol infusion rate to achieve the desired anaesthesia depth, whereas TCI-pumps deliver propofol using inbuilt algorithms based on the pharmacokinetic (PK) and pharmacodynamic (PD) profile of propofol. Two of the most used PK-PD models for propofol delivery are the Marsh model and the Schneider model. Whereas in the Marsh model the user can set the desired target plasma concentration, Schneider model allows the user to set the desired target effect site concentration for achieving adequate depth of GA. Over the last two decades the evolution and advancement in automated anaesthesia delivery systems, particularly for propofol administration, has made propofol-TIVA delivery more efficient by removing the human interface required for adjusting real-time propofol delivery, both rate and concentration of propofol. Automated anaesthesia delivery systems deliver propofol based on ascertaining frontal cortex electrical activity as determined by the processed electroencephalogram, the bispectral index (BIS) score. These devices regulate propofol delivery based on a feedback loop involving the BIS score (control variable) generated by the patient and the propofol infusion pump (actuator) and attempts to keep the values within a pre-assigned range, consistent with robust GA depth. Closed loop anaesthesia delivery system (CLADS) is an indigenously developed patented (Patent no.502/DEL/2003 & US 9,108,013 B2) computer-controlled anaesthesia delivery system which works with feedback loop information elicited by BIS monitoring and delivers propofol TIVA to the patient via a non-TCI automated infusion pump. The basic control algorithm is based on the relationship between the infusion rates of propofol and BIS values, taking into consideration the pharmacokinetic variables, such as, drug distribution and clearance. The system updates the EEG data every 5-seconds and calculates the BIS error, a difference between the target BIS and the actual BIS value using the proportional-integral-derivative (PID) controller. During anaesthesia induction the target concentration is achieved in a stepwise manner with BIS feedback received every 5-seconds. During maintenance phase of anaesthesia, the propofol delivery is modified every 1-epoch of 30-seconds duration. In each epoch an average of initial 3-BIS values (of every 5-seconds) and average of last 3-BIS values (of every 5-seconds) are compared, and a trend assessment is made. If the trend indicates increasing BIS values, then higher propofol rate is delivered by the infusion pump (actuator) and vice-versa. The control algorithm is implemented using a personal computer (PC) with a Pentium 4 processor. The PC controls communication with the infusion pump (Pilot-C, Fresenius, Paris, France) and the vital sign monitor (AS5, Datex Ohmeda Division, GE Healthcare, Singapore) through RS 232 serial ports. CLADS has been extensively used and validated for administering propofol TIVA in patients undergoing both cardiac and non-cardiac surgical procedures. In a multi-centric study on evaluation of anaesthesia delivery by CLADS, it was shown that CLADS maintains depth of anaesthesia with far more precision as compared to manual administration. A new compact and upgraded version of CLADS (Clarity Medical Private Ltd., Mohali, Punjab Indiais now available. The new version integrates the anaesthetic depth as well as the hemodynamic monitor, the controller, the user interface and the actuator syringe pump into a single, compact and user-friendly module. The investigators aim to conduct a prospective randomised pilot to compare the multiple connected-unit conventional CLADS with the hermetically unit-integrated CLADS version, with respect to, the adequacy of anaesthesia depth (primary objective); and, performance characteristic, propofol requirement, haemodynamic stability, recovery from anaesthesia and postoperative sedation of the delivery systems (secondary objectives).

Evaluation of Propofol Dosing Based on Total Body Weight Using Closes-loop Anaesthesia Delivery System

Propofol is the most used intravenous agent for induction and maintenance of anaesthesia as part of total intravenous anaesthesia (TIVA) regimen. In the morbidly obese, various factors, such as, increased body fat content, lean body weight, cardiac output, total blood volume, and alterations in regional blood flow; which adversely/unpredictably affect the volume of distribution, clearance and elimination of intravenous anesthetic drugs, thereby making administration of TIVA difficult to control. A major concern with propofol dosing based on total body weight (TBW) in the obese patients is disproportionate drug administration leading to undue drug accumulation in body with potential overdosing, delayed recovery from anaesthesia, and adverse hemodynamic outcome. Studies on propofol dose regimen for TIVA recommended that LBW should be used for calculating bolus dose during induction of anaesthesia and TBW or ABW for arriving at a infusion dose required for maintenance of anaesthesia. Propofol requirement for induction of anaesthesia is based on LBW is especially relevant for the morbidly obese patients as because their surplus fat mass increases volume of distribution of propofol, which, in the face of decreased blood flow to adipose tissue; imposes the burden of potential drug accumulation. This may result in increased drug delivery to non-adipose tissue during induction of anaesthesia and possibly leading to undesirable rarefaction of depth-of-anaesthesia and attendant adverse haemodynamic effects. Conversely, during the maintenance phase of propofol TIVA, the volume of distribution and clearance of propofol increases and correlates linearly with TBW. In this respect, controlling propofol delivery in the morbidly obese with Eleveld allometric PK model, which utilizes TBW as weight parameter; has been found to be superior to other models that employs other weight dosing scalars. The use of ABW in Schnider and Marsh model takes into consideration drug distribution to lean tissues as well as a proportion to the body fat weight, thus accounting for lipid solubility dynamics of propofol. ABW is calculated by adding 40% excess fat weight (FW) to IBW. In obese patients propofol delivery using the Eleveld allometric PK model by incorporating TBW has been found to be superior to other models using other dosing scalars. Target-controlled infusion (TCI) forms the core of standard-of-care method used for administration of propofol TIVA. TCI system typically includes a microprocessor-controlled syringe pump that is designed to achieve a defined plasma concentration of the drug based on patient response and multi-compartment pharmacokinetic (PK) model. While TCI systems are designed to deliver propofol at a rate based on a predetermined plasma concentration, they do not take into consideration patient's pharmacodynamic profile. Hence, it is difficult to determine whether the target plasma concentration achieved has produced adequate anaesthesia depth. In the absence of reliable depth of anaesthesia monitors, during the maintenance phase of propofol TIVA, the desired plasma concentration achieved may either result in intraoperative awareness due to under-dosing or delayed recovery from anaesthesia because of over-dosing. Currently, an array of research on automated propofol delivery using computer-controlled closed loop anaesthesia delivery systems which deliver propofol based on patient's frontal cortex electrical activity as determined by bispectral index (BIS); have amply exhibited that these systems deliver propofol and maintain depth of anaesthesia with far more precision as compared to manual administration. Liu et al used a BIS-guided dual loop anaesthesia delivery system to determine requirement of propofol and remifenatnil in the obese versus lean patients. The propofol delivery was controlled by a closed loop set through TCI pump. Propofol was delivered with dose calculation by TBW and based on the Schnider model. The propofol dosage delivered as per TBW in real-time was analyzed post hoc on a IBW scale. The propofol requirements for induction and maintenance based on TBW was equivalent both in obese and lean patients. CLADS is a BIS-guided automated closed-loop anaesthesia delivery system developed by Puri, which delivers propofol using a non-TCI infusion pump. This system uses a control algorithm that is based on the relationship between diverse rates of propofol infusion and BIS variable. CLADS regulates the propofol infusion rate to maintain a predetermined BIS target (BIS=50) and is independent of plasma propofol concentration status. CLADS is uniquely versatile in that it can calculate propofol dosage delivered both on basis of TBW or IBW. Whereas, in a study comparing CLADS administered propofol versus desflurane-GA in morbid obese patients undergoing bariatric surgery (unpublished data) the propofol maintenance dosage based on ABW was 5.5 + 1.3 mg kg-1 h-1; Liu et al reported a median propofol consumption of 5.2 [4.1, 6] mg kg-1 h-1 with their dual-loop closed loop anaesthesia delivery system that also utilized TBW based administration of propofol and remifentanil. In both the study, BIS was used as an input control actuator to close the feedback loop joining the patient, the delivery system, and the infusion flow system. Although maintenance of propofol TIVA based on TBW is well established, the dosing schedule based on ABW is not well explored. Since the ABW takes into consideration a certain percentage of FW in addition to IBW and not the complete FW as in TBW, we hypothesize that propofol dosing using ABW will result in lower propofol requirement as compared to TBW for maintaining equivalent anesthetic depth. Since CLADS gives an objective assessment of propofol dose delivered and anaesthesia depth consistency, this randomized study aim to compare the maintenance requirements of propofol in obese patients given propofol dosing based on TBW versus ABW

Propofol Versus Sevoflurane for Induction of GA in Infants

This study aims to investigate the hemodynamic effects of both propofol and sevoflurane for induction of anesthesia in infants less than 3 months of age by electrical cardiometry. The investigators hypothesized that propofol will have a safe hemodynamic profile for induction of anesthesia in infants less than 3 months of age as measured by electrical cardiometry in addition to its favorable pharmacokinetic profile of rapid induction and optimal intubation conditions.It is conducted at Abu Al Reesh Children's Hospital, Faculty of Medicine, Cairo University based on an institutional protocol used as a standard of care to induce anesthesia

Comparison of TIVA by Closed Loop Anaesthesia Delivery System Versus Target Controlled Infusion Device

Inhalation anaesthetic were backbone of general anaesthesia (GA) practice till the time an intravenous anaesthetic, propofol was introduced in early 1970's and its commercial availability in 1980's, which led to the resurgence in the practice of total intravenous anaesthesia (TIVA). TIVA is now being adopted as a preferred technique for providing GA because of scores of inherent advantages, like, reduced PONV incidence, improved quality of post-anaesthesia recovery, anti-inflammatory and anti-oxidant action, anti-neoplastic activity, analgesic action, and absence of greenhouse effect among many others.Over the years propofol-TIVA delivery has become more methodical and precise owing to the use of target controlled infusion (TCI) systems. TCI systems use propofol pharmacokinetic (PK) or pharmacodynamics (PD) models which predict either the plasma or the effect-site propofol concentration required for maintenance of GA steady-state during surgery. The 'Diprifusor' TCI-system was the first commercially available propofol TCI-system. The 'Diprifusor' TCI-system was a 'closed' TCI-system which required a special electronically tagged pre-filled propofol syringe to be attached to the TCI-pump. The current TCI technology has evolved with the introduction of the 'open' TCI concept wherein syringes of any configuration can be attached to the TCI-pumps having pre-programmed propofol PK-PD models. Currently, the two most commonly used PK-PD models that drive TCI systems to deliver TIVA are the 'Marsh' and 'Schneider' models. Whereas Marsh model targets blood plasma concentration of propofol for anaesthesia maintenance, the Schneider model targets effect-site concentration in the brain. A recent advance in propofol TIVA delivery has been the development of automated closed loop anaesthesia delivery system. These devices deliver propofol based ascertaining patient's frontal cortex electrical activity as determined by bispectral index (BIS) score and then keeping the values within a pre-assigned range consistent with robust GA depth. Closed loop anaesthesia delivery system (CLADS) is an indigenously developed patented (502/DEL/2003) computer-controlled anaesthesia delivery system. CLADS typically works with feedback loop information elicited by BIS monitoring and delivers propofol TIVA to the patient via a non-TCI automated infusion pump. This basis of CLADS is the control algorithm based on the relationship between diverse rates of propofol infusion and the processed EEG variable. Although propofol delivery by CLADS is based on pharmacokinetic model but for greater precision and efficient administration, its delivery trigger is directly linked with feedback mechanism involving patient's EEG profile as monitored by the BIS scores. In a multicentre study on evaluation of anaesthesia delivery by CLADS, it was shown that CLADS maintains depth of anaesthesia with far more precision as compared to manual administration. Queerly while TCI & CLADS technology evolved over a period of time; there is no data available comparing the efficacy of TCI delivered propofol-TIVA versus automated propofol delivery systems. Based on additional feedback loop incorporated to the PK-PD model the investigators contend that automated propofol TIVA as administered by CLADS is likely to be superior to TCI system in achieving and sustaining anaesthesia depth. This randomized controlled study aims to compare the efficacy of CLADS-driven propofol TIVA versus TCI administered propofol TIVA in adult patients undergoing non-cardiac surgery with respect to: adequacy of anaesthesia depth maintenance (primary objective), performance characteristic of propofol delivery system, propofol requirement, hemodynamic stability, recovery from anaesthesia and postoperative sedation (secondary objectives).

Modeling and Closed-loop Control of Depth of Anaesthesia

Scientific background An increasing degree of automation and informatisation of dynamical processes enables higher quality of achieved goals, lower costs and lower eventual impact on humans and nature alike. Automatic control is an infrastructural field that comprises mathematical modelling, simulation of dynamical systems and automatic control methods. The systematic approach enables the use of control methods in various technical and nontechnical fields, therefore, the advances in automatic control are very useful in interdisciplinary projects. Likewise, there are many processes in medicine that can be improved by automatic control. In the literature, there have been some approaches to closed-loop control of depth of anaesthesia, but none seem to have influenced clinical practice. Within the project the investigators will develop a system for closed-loop control of depth of anaesthesia using BIS index, which will be based on a predictive model and will consider individual properties of each patient that are obtained from the measurements. Problem identification To perform a general anaesthesia, it is necessary to use substances, which enable deep unconsciousness, analgesia, amnesia and muscle relaxation, all required for performing a surgery or a diagnostic procedure. General anaesthesia and related dynamic activities in the human body is a complicated process, which includes pharmacokinetic and pharmacodynamic mechanisms, which have not been fully studied yet. During the general anaesthesia the anaesthesiologist needs to monitor the patient's vital functions and maintain the functions of vital organs. To achieve anaesthesia, substances are introduced in different manners into the patient's body. In clinical practice, the most commonly used methods are the intravenous induction of an anaesthetic agent, i.e., injection of the anaesthetic into a vein, and inhalation induction of anaesthesia, whereby the patient inhales the substance from the breathing mixture. Total intravenous anaesthesia (TIVA) is an anaesthesiologic technique, where substances are injected intravenously. The anaesthesiologist needs to adjust the dosage of anaesthetic to maintain the appropriate depth of general anaesthesia according to pharmacokinetics and pharmacodynamics of the anaesthetic agent and considering the type of procedure. Inadequate depth of anaesthesia is manifested with the activation of sympathetic nerves or in the most unlikely event with the patient awakening. Too deep anaesthesia is manifested with a drop in blood pressure level and heart rate frequency as well as slow post-operative awakening of the patient from general anaesthesia. In modern clinical practice, the depth of anaesthesia is determined by assessing the relevant clinical signs (iris, sweating, movements), by interpreting hemodynamic measurements and by estimating the depth of anaesthesia from EEG signals, for which several established measurement systems already exist, e.g. BIS index, Narcotrend, Scale Entropy, Response Entropy, Cerebral State Index, Patient State Analyser, Similarity index, Surgical Stress Index, Auditory Evoked Potential, Patient State index (PSi). BIS index measurement is a non-invasive method, where a BIS monitor is connected to electrodes on the patient's head. By measuring the EEG signals the bispectral index is defined, representing the depth of anaesthesia. The BIS monitor provides a single dimensionless number, which ranges from 0 (equivalent to EEG silence) to 100. A BIS value between 40 and 60 indicates an appropriate level for general anaesthesia, whereas for long-term sedation due to head injuries a value below 40 is appropriate. The reference can thus be set to the applicable value; the manner and speed of approaching the reference value depend on the specific characteristics of the procedure and the pharmacokinetics and pharmacodynamics of the substance in the patient's body. A novel very promising depth-of-anaesthesia measuring method based on EEG signals is Patient State Index (PSi). The forehead sensor collects the patient's EEG data from the frontal lobe on both sides of the brain, which is an advantage of the PSi method. The PSi measuring system features an enhanced signal-processing engine, which provides the PSi calculation with a minimal delay. The calculated index represents a processed EEG-based variable related to the effect of the anaesthetic agents. For general anaesthesia, a PSi value between 25 and 50 is considered appropriate. Objective of the proposed research with particular emphasis on the originality of the proposed research and its potential impact for the development of new research directions The anaesthesiologist adjusts the injection of intravenous anaesthetic agents regarding the depth of anaesthesia. The closed-loop system for administration of intravenous anaesthetic agent will enable immediate reaction and adjustment of the intravenous anaesthetic flow. In this project the investigators will focus on the closed-loop control of flow in intravenous administration of propofol . Induction of propofol affects the EEG index and an adequate controller sets the infusion pump so that the EEG index follows as closely as possible the trajectory, prescribed by the anaesthesiologist. The proposed research project is divided in two parts: - the development of a mathematical model describing the impact of anaesthetic-agent administration on the depth of anaesthesia (EEG index); - the development of a closed-loop control system for depth of anaesthesia. The first phase will begin with the modelling of dynamics of anaesthetic-agent administration impacting the anaesthetic depth. The advantages of developing a mathematical dynamical model are as follows: better comprehension of the process and its dynamics; the model presents the basis for developing a simulator and for running simulation experiments that are useful in the closed-loop control-system design phase; the dynamical mathematical model can be employed in the control algorithm, especially for predictive control approaches. Inadequate depth of anaesthesia is manifested with the activation of sympathetic nerves
 or in the most unlikely event with the patient awakening. Too deep anaesthesia is
 manifested with a drop in blood pressure level and heart rate frequency as well as slow
 post-operative awakening of the patient from general anaesthesia. In modern clinical
 practice, the depth of anaesthesia is determined by assessing the relevant clinical signs
 (iris, sweating, movements), by interpreting hemodynamic measurements and by estimating
 the depth of anaesthesia from EEG signals, for which several established measurement
 systems already exist, e.g. BIS index, Narcotrend, Scale Entropy, Response Entropy,
 Cerebral State Index, Patient State Analyser, Similarity index, Surgical Stress Index,
 Auditory Evoked Potential, Patient State index (PSi). BIS index measurement is a
 non-invasive method, where a BIS monitor is connected to electrodes on the patient's
 head. By measuring the EEG signals the bispectral index is defined, representing the
 depth of anaesthesia. The BIS monitor provides a single dimensionless number, which
 ranges from 0 (equivalent to EEG silence) to 100. A BIS value between 40 and 60 indicates
 an appropriate level for general anaesthesia, whereas for long-term sedation due to head
 injuries a value below 40 is appropriate. The reference can thus be set to the applicable
 value; the manner and speed of approaching the reference value depend on the specific
 characteristics of the procedure and the pharmacokinetics and pharmacodynamics of the
 substance in the patient's body. A novel very promising depth-of-anaesthesia measuring
 method based on EEG signals is Patient State Index (PSi). The forehead sensor collects
 the patient's EEG data from the frontal lobe on both sides of the brain, which is an
 advantage of the PSi method. The PSi measuring system features an enhanced
 signal-processing engine, which provides the PSi calculation with a minimal delay. The
 calculated index represents a processed EEG-based variable related to the effect of the
 anaesthetic agents. For general anaesthesia, a PSi value between 25 and 50 is considered
 appropriate.
 
 Objective of the proposed research with particular emphasis on the originality of the
 proposed research and its potential impact for the development of new research directions
 
 The anaesthesiologist adjusts the injection of intravenous anaesthetic agents regarding
 the depth of anaesthesia. The closed-loop system for administration of intravenous
 anaesthetic agent will enable immediate reaction and adjustment of the intravenous
 anaesthetic flow. In this project the investigators will focus on the closed-loop control
 of flow in intravenous administration of propofol . Induction of propofol affects the EEG
 index and an adequate controller sets the infusion pump so that the EEG index follows as
 closely as possible the trajectory, prescribed by the anaesthesiologist.
 
 The proposed research project is divided in two parts:
 
 - the development of a mathematical model describing the impact of anaesthetic-agent
 administration on the depth of anaesthesia (EEG index);
 
 - the development of a closed-loop control system for depth of anaesthesia.
 
 The first phase will begin with the modelling of dynamics of anaesthetic-agent
 administration impacting the anaesthetic depth. The advantages of developing a
 mathematical dynamical model are as follows: better comprehension of the process and its
 dynamics; the model presents the basis for developing a simulator and for running
 simulation experiments that are useful in the closed-loop control-system design phase;
 the dynamical mathematical model can be employed in the control algorithm, especially for
 predictive control approaches.
 
 The input of the controller is represented by two signals: the reference value of EEG index and the actual value of EEG index. The controller uses these two signals to calculate the suitable input signal of the infusion pump, which administers propofol with a flow set by the controller. Once the propofol is administered into the body, its level in blood increases and consequently the concentration at the effect site, i.e. central nervous system, increases, too. Changing of the propofol concentration is a dynamic process, which depends on the pharmacokinetic system of the patient. The concentration level of propofol at the effect site represents the input of pharmacodynamic system, describing the depth of anaesthesia, which could be treated as the output of pharmacodynamic system. The depth of anaesthesia affects the brain waves, measured by electrodes for measuring EEG signals. The EEG monitor measures the signals and uses these measurements to establish the EEG index. The induction of other anaesthetic agents (e.g. remifentanil analgesic), which also partially impacts the EEG index, is considered as a disturbance. The originality of the expected results In this project, the depth of anaesthesia will be treated from 3 perspectives: modelling, simulation, and control. The problem of modelling the effect of propofol is described in literature in various ways. Pharmacokinetic and pharmacodynamic models, such as Marsh, Schneider, Kataria, Schüttler, White-Kenny have been developed for such purposes. The models typically define the basic structure of the dynamic operating system of propofol and the parameters depend on individual patients. The values of model's parameters are affected by the patient and his characteristics (weight, height, age, sex etc.) as well as individual sensitivity to propofol and the ability to excrete propofol. A mathematical model of propofol affecting the dynamics of depth of anaesthesia will be developed based on the existing models in literature. The investigators will develop the model using classic modelling approaches, such as differential equations with the Laplace-domain and state-space representations, as well as advanced approaches: nonlinear dynamics will be treated using fuzzy logic, namely Takagi-Sugeno models. An appropriately validated dynamical model for propofol activity will be the basis for developing a simulator assisting the anaesthesiologist in safe study of anesthesiologic procedures. It will simplify the understanding of the operating mechanism of propofol and enable testing of different scenarios of administering propofol. Several developed pharmacokinetic models are used in certain infusion pumps for target controlled infusion (TCI), where the pump sets the proper flow of the medication with regard to the model. The problem with these models is that they often do not reflect the real dynamics, which also depends on individual sensitivity of the patients to the substance, therefore such approaches, based on open-loop induction, often do not yield the best performance. The algorithm for closed-loop control of anaesthetic depth will be based on 2-DOF control, which means that it can be functionally divided into two parts: the feedforward and the feedback part. Hence, the algorithm merges the advantages of both open-loop and closed-loop control. The feedforward part will use the model of propofol to calculate the flow according to EEG index reference trajectory. On the other hand, the feedback part will provide the appropriate flow corrections based on EEG index measurements. The advantage of the proposed approach is that the feedforward part of the control algorithm can bring the actual EEG index value close to the reference trajectory, whereas the feedback part compensates the control error, which occurs due to inaccurate modelling, noise and eventual disturbances on the real system, such as for instance the induction of remifentanil. The control algorithm will be based on the developed dynamic model of propofol that will be used for predicting the depth of anaesthesia. By online adaptation of the parameters of the internal dynamic model, the algorithm will consider the individual patient's response to propofol, estimated from the measurements during the procedure. Working methods The project work will begin with modelling and simulation studies of propofol effects. The modelling procedure will involve theoretical and experimental approaches. Within the theoretical modelling framework, the investigators will use the knowledge on pharmacokinetic and pharmacodynamic mechanisms, whereas the experimental approach will complement the theoretical one by using the appropriate measurements for identifying the structure and the parameters of the model. Mathematical modelling of complex systems is an iterative procedure, requiring verification and validation of the developed model in every consecutive step. The quality of the data, obtained from suitably designed experiments, is of utmost importance. The measured signals must be properly synchronized, appropriately filtered, sampled and informationally-adequate segments have to be selected for identification. The developed model will be tested in the Matlab-Simulink environment. The virtual simulation environment will enable various experiments for validation of the model behaviour and comparison to the measured dynamics of depth of anaesthesia. The investigators will develop a user interface that will facilitate the conduction of simulation experiments. The developed system for closed-loop control of depth of anaesthesia will be first tested in a virtual environment. Finally, the investigators will also test it - under anaesthesiological supervision - in clinical practice. The anaesthesiological protocol with detailed descriptions of the course of operation and induction of particular agents is described in the application that is being considered at the National Medical Ethics Committee of Slovenia. Due to space restrictions the aforementioned details are not stated here. Relevance and potential impact of the results Despite the obvious advantages of closed-loop control of anaesthetic depth, such approaches are not yet used in clinical practice. Hence, the main result of this project will be the development and the study of implementation potential of closed-loop control system for depth of anaesthesia, based on EEG index measurements. In the first part of the project the investigators will develop dynamical model dealing with the effects of anaesthesiological agents on the depth of anaesthesia, whereas the second part will be devoted to the development of a system for closed-loop control of depth of anaesthesia. The developed model will be validated by comparing its outputs it to the measurements of dynamical processes on real patients. Finally, the performance of the closed-loop control system will be assessed in clinical practice. We expect that by using the proposed concept of closed-loop control of depth of anaesthesia, which is measured by EEG index and controlled by propofol administration, a better course of depth anaesthesia than in manual operation will be achieved. The control system will avoid excessive overshoots of EEG index trajectory, react instantly to unexpected dynamic behaviour, effectively compensate disturbances and consider a priori unknown pharmacokinetic and pharmacodynamic properties of a particular patient. On the other hand, the anaesthesiologist will be notified only in cases of unpredicted value of EEG index or propofol flow outside the prescribed constraints. In such a manner, the anaesthesiologist will be able to devote his attention to other critical aspects of anaesthesia. Although the anaesthesiologist will not have to continuously monitor the EEG index value, the automatic system will decrease the deviation of depth of anaesthesia from the desired value. Improved tracking of the reference trajectory will certainly be beneficial for the patients as it will decrease the possibility of being awake during the procedure and at the same time prevent excessive administration of propofol, which will ease the postoperative recovery and adverse events of propofol. It will also decrease the amount of propofol used during the procedure. Exceptional socio-economic or culturally relevant achievements of the project leader The main field of research of the project leader Assist. Prof. Dr. Gorazd Karer are modelling, simulation and control of dynamical systems. Since his PhD defence in 2009 he has been intensively working especially on advanced approaches to mathematical modelling and on control of dynamical processes. He is the author or co-author of 16 scientific papers, 28 conference papers, 1 scientific monograph, 1 chapter in a scientific monograph, 1 terminological dictionary, 3 studies and the supervisor of 14 successfully defended bachelor theses. He is involved in several courses in the field of modelling, system theory and automatic control at the Faculty of Electrical Engineering, University of Ljubljana. The courses Automatic Control Systems and Automatic Control are the basic courses in the Control Engineering study programme. The courses Control Systems Instrumentation and Control Technology Instrumentation deal with technological aspects and sensors. The courses Modelling and Signal Processing and Modelling Methods treat modelling of dynamical systems. The approaches from the latter will be useful especially for the first stage of the research project. In 2013, he published a scientific monograph with Springer Verlag titled Predictive Approaches to Control of Complex Systems with his co-author Prof. Dr. Igor Škrjanc. The monograph has been favourably accepted in the scientific community as it has been downloaded in electronic form more than 11.000 times since it had been made available online at Springer. The monograph deals with advanced control algorithms for systems with complex dynamics, which also include the dynamic processes during anaesthesia. Therefore, the approaches described in the monograph represent an excellent basis for the development of a system for closed-loop control of depth of anaesthesia proposed in this project. He was the initiator and one of the authors of the Dictionary of automatic control, systems and robotics, published in 2014. In the preparation phase, the Terminological Section of the Fran Ramovš Institute of the Slovenian Language at the Research Centre of the Slovenian Academy of Sciences and Arts (ZRC SAZU) was involved. During the project he was intensively working on the terminological definitions of concepts from his research field. Such a terminological experience facilitates the communication in interdisciplinary teams, especially with co-workers that are not familiar with the field of automatic control. Therefore, it will also benefit the cooperation with anaesthesiologist involved in the proposed project. He was the secretary of the Automatic Control Society of Slovenia from 2010 to 2014 and has been a member of the Executive Committee since 2014. The contacts within the society enable connections to the experts working in the field of automatic control both in academia and in industry, which provides a good overview of the state of automatic control in Slovenia. He was involved in the Competence Centre for Advanced Control Technologies, where a control approach, based on key performance indicators (KPI) and dynamic model identification was developed. The approach is conceptually related to the proposed closed-loop control system for depth of anaesthesia. The methods for acquiring knowledge from the history of KPI will also be useful for developing the proposed control system, of course by considering the anaesthesia-related particularities and by involving the knowledge of the collaborating anaesthesiologists. Organisational structure and feasibility of the project The project will be realized in collaboration with a research group at the Department of Anaesthesiology and Surgical Intensive Therapy (KOAIT) at the University Medical Centre (UKC) Ljubljana, led by Boris Počkar. The group consists of anaesthesiologists that have access to the equipment needed for the theoretical results of the project and the simulation studies to be clinically validated. The clinical part of the research will be carried out at the Department of Ophthalmology UKC Ljubljana for vitroretinal surgeries, at the Neurosurgical Department UKC Ljubljana for patients undergoing surgery due to expansive processes in the head, and at the Intensive Care Unit KOAIT UKC Ljubljana for patients needing long-term sedation due to head injuries. For establishing the plasmatic concentrations of anaesthetic agents the investigators will cooperate with the Institute of Clinical Chemistry and Biochemistry UKC Ljubljana. The first measurements will be conducted after obtaining the approval from the National Medical Ethics Committee of Slovenia.

Efficacy of Dexmedetomidine-Propofol Versus Ketamine-Propofol for Sedation

The Safety of Etomidate - Propofol Mixture vs Propofol in Total Intravenous Anesthesia During Abdominal Surgery

Total intravenous anesthesia (TIVA) is one of the common anesthesia maintenance methods in clinic. Intravenous anesthetics commonly used in clinical practice include propofol and etomidate, both of which have their own advantages and disadvantages. Among them, propofol has the advantages of rapid onset, complete sedation and rapid recovery, but it is easy to cause injection pain. Moreover, the inhibitory effect of propofol on the circulatory system is more obvious, and the incidence of hypotension during propofol use in TIVA is higher. In contrast, intraoperative hypotension substantially increases the risk of perioperative adverse cardiovascular and cerebrovascular events. Etomidate, a derivative of imidazole, reversibly increases GABAA receptor activity and inhibits synaptic transmission and impulse transmission, resulting in sedation. Etomidate has a rapid onset of action, minimal hemodynamic effects, and a shorter dose-related half-life than propofol; however, etomidate has a suppressive effect on the adrenal cortex. Several studies have confirmed transient suppression of adrenocortical function with a single injection or continuous pump of etomidate, with recovery of preoperative baseline adrenocortical function within 48 hours after surgery. Combined drugs can reduce the adverse reactions caused by single drugs. Considering the complementary effects of propofol and etomidate in pharmacodynamic characteristics, the combination of propofol and etomidate is beneficial to maximize their respective advantages and reduce adverse reactions. Intraoperative hypotension is a common complication during general anesthesia, and severe hypotension is closely related to perioperative cardiovascular complications and stroke ; therefore, avoiding perioperative hypotension is the basic premise to ensure patient safety. Abdominal surgery is a common type of general surgery, with a large number of operations and relatively uniform operation time, which is easy to collect cases. Therefore, this study aims to investigate the effect of propofol-etomidate mixture used in TIVA on the incidence of hypotension during anesthesia induction and maintenance in adult patients undergoing elective abdominal surgery, in order to provide an alternative, safe, reasonable and easy to promote medication regimen for total intravenous anesthesia.

Comparison of the Effects of Esketamine, Sufentanil, or Lidocaine on Tussis Reflection During Upper Gastroscopy

The patients are selected according to their inclusion and exclusion criteria for diagnostic upper GI endoscopy and informed consent. The patients will be divided into the four groups: P group (single administration of propofol), P + S group (administration of propofol and sufentanil in combination), P + K group (administration of propofol and esketamine in combination), and P + L group (administration of propofol and lidocaine in combination) (N = 100 per group). Baseline information will be collected and recorded before the operation. Anaesthetic drugs will be prepared by the nurses and anaesthetists on the day of the operation as follows: 0.9% normal saline (20 mL) for the P group, 0.5 μg/mL sufentanil (20 mL) for the P + S group, 1.5 mg/mL esketamine (20 mL) for the P + K group, and 10 mg/mL lidocaine (20 mL) for the P + L group. Before entering the operating room, the patients will be given lidocaine defoamer for gargling to open the upper limb vein and 5 mL/min Lactate Ringer solution. After entering the room, the patients will wear masks to inhale high-flow oxygen, and their vital signs will be monitored and recorded as Tire. Analgesic drugs (diluted to 20 mL according to different concentrations) prepared by the nurses will be slowly injected into their veins 5 min before examination for 30 s (the dose was calculated using the formula: the injected drug dose (ml) = the weight of the patient (kg)/10"; 1.5 mg/kg propofol will be intravenously administrated. . Multiple-dose administration is acceptable according to the state of the patient. The endoscope will be inserted when the eyelash reflex disappeared (sedation depth grade: deep sedation). Blood pressure will be recorded after every 3 min from the beginning of the examination, and HR, SpO2, and RR will be recorded simultaneously. The frequency and degree of tussis, nausea, and vomiting and/or body movements at endoscope insertion or within 5 min of insertion will be monitored. In case of any abnormalities, they should be described in detail, and appropriate doses of propofol should be added until the endoscope exits the teeth pad. During endoscopy, 2-4 mL of propofol should be added under the conditions of extended operation time, accelerated breathing, and elevated blood pressure and heart rate to maintain deep sedation. The patients will be transferred to a recovery room after the operation, and their vital signs will be recorded after every 5 min until the patients met the standard of leaving the hospital (Steward score ≥ 4) before discharge