Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03569839 |
| Other study ID # |
0120-438/2017 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 14, 2017 |
| Est. completion date |
December 2025 |
Study information
| Verified date |
December 2023 |
| Source |
University of Ljubljana |
| Contact |
Gorazd Karer |
| Phone |
+386 1 4768701 |
| Email |
gorazd.karer[@]fe.uni-lj.si |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The study evaluates the effect of anaesthetic agents to depth of anaesthesia. An improved
PK-PD model wil be developed that will provide the basis for understanding the mechanisms,
simulating various scenarios and developing algorithms for better and safer administration of
anaesthetic agents.
Description:
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.
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.
