Zheng Hong, Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University

　　In the past ten years, the technology of intravenous anesthesia has developed rapidly, especially the emergence of short-acting, non-accumulated intravenous anesthetics and the improvement of the target controlled infusion system (TCI), which has brought total intravenous anesthesia (TIVA) to a new level. . Although modern infusion systems have made significant advances, they are far behind in terms of theoretical and practical application convenience compared with dedicated volatilization devices for inhaled anesthetics. Achieving the same clinical convenience and pharmaco-pharmacodynamic accuracy as inhaled anesthetic vaporizers may be the ultimate goal of the development of intravenous anesthetic infusion systems. To achieve this goal, the modern pharmacokinetic-pharmacodynamic concept must be combined with a computer-controlled infusion system.

　　This article aims to summarize the history of the development of intravenous anesthetic infusion systems (compared with the volatilization device of inhaled anesthetics), and use the computer-controlled infusion pump (TCI) as an "intravenous vaporizer" to describe the current development. State, put forward some new concepts and predict future development trends.

　　1. Historical background

　　The development process of intravenous anesthetic infusion system is a relatively slow and long process, and its main development process spans four centuries. 　　

       1. After Christopher Wren used a feather stem to inject opium into a human vein for the first time in 1657, Harvey’s then described the human circulatory system and first directly administered the drug through the circulatory system. More than two centuries later, French Rynd invented a vacuum needle with a syringe to make intravenous administration more convenient. With the further understanding of the circulatory system and intravenous route of administration, the initial development of the infusion system mainly focused on how to accurately inject fluids. The combination of a syringe and an infusion device driven by gravity has been the main infusion method for a long time. 　　

       2. The climax of the development of the infusion system is the computer-controlled infusion pump invented in recent years, with high accuracy, convenient application, and automatic calculation. It can complete very complex calculation operations. For this infusion system, more recent research has focused on how to perfectly combine computer-assisted infusion technology with modern pharmacodynamics to achieve the expected pharmacodynamic effects. Based on modern pharmacokinetic room-compartment model theory, the population pharmacokinetic parameters are embedded in the program to control the infusion system to adjust the infusion rate at any time, and to obtain the corresponding target plasma and/and target effect chamber drug concentration through calculation and analysis Has become a reality. The calculated infusion rate of the infusion pump should be consistent with the expected plasma drug concentration or effect chamber concentration desired by the user ("open-loop" control). 　　

       3. Similarly, the closed-loop target-controlled infusion system has further developed the perfect combination of computer-controlled infusion technology and modern pharmacology to obtain the accuracy of pharmacokinetics. Using a complete pharmacokinetic-pharmacodynamic model, the infusion system can change the infusion rate in real time according to the body's feedback effect on the drug. Therefore, TCI forms a closed loop between pharmacodynamics and pharmacokinetics. The anesthesiologist adjusts the depth of anesthesia in time according to the needs of the operation and the patient through the combination of the pharmacodynamic-pharmacodynamic model of the closed-loop infusion system. 　　

       2. Comparison of intravenous anesthetic infusion system and inhaled anesthetic infusion system 　　

       1. Inhalation anesthetics enter the brain through a volatilization tank with a standard scale and need to pass through the respiratory tract, alveolar membrane, and blood flow; through complex mechanisms such as diffusion, distribution, and dissolution. Therefore, it has many basic advantages, because the inhaled anesthetic enters the circulatory system indirectly through the lungs, (in Figure 26A-2) the balance formed by the gas across the alveoli to the pulmonary capillary network blocks the continuous absorption of the drug. As a balance of the partial pressure between the alveoli and the pulmonary capillary network, the intake of inhaled anesthetics will gradually decrease. Inhalation according to the scale set by the volatilization tank can proportionally reflect the drug effect point of the inhaled anesthetic in the central nervous system and the concentration in the blood. On the other hand, due to the process of partial pressure balance, the partial pressure of the inhaled anesthetic agent in the blood cannot exceed the partial pressure of the inhaled anesthetic gas, so that relatively accurate administration is possible. Furthermore, modern respiratory gas monitoring equipment can measure and verify the concentration of the drug in the exhaled breath to ensure the accuracy of the pharmacodynamics. Finally, the clinical significance of the measured concentration of inhaled anesthetics can be described by the minimum alveolar concentration (MAC) and provides the accuracy of pharmacokinetics. 　　

       2. In contrast, intravenous anesthesia allows the drug to enter the circulatory system directly, and there is no barrier to prevent inaccurate drug absorption. In fact, there is a great danger latent. Therefore, without the help of computer models, it is impossible to know the intravenous anesthetic infusion rate and the corresponding measured blood concentration, and it is impossible to accurately administer the drug according to the body's feedback effect. Furthermore, the current biochemical technology is still unable to measure the blood concentration of intravenous anesthetics in real time, which hinders the accuracy of pharmacodynamics at the same time point. Finally, even if the blood concentration of intravenous anesthetics can be measured clinically in real time, the clinical effect caused by this concentration has not been clarified, especially the monitoring of analgesia cannot be accurately quantified and qualitatively. In other words, for intravenous anesthetics, thorough research and extensive simulation of MAC are not advisable. Therefore, it is currently impossible to achieve the same accuracy as the pharmacokinetics of inhaled anesthetics. 　　

       3. At present, because there is no intravenous anesthetic infusion system that can be compared with the vaporizer of inhaled anesthetic. Therefore, anesthesiologists have not yet formed the habit of thinking that administering intravenous anesthetics according to the plasma drug concentration and the degree of surgical stimulation that matches the desired depth of anesthesia, just like applying inhaled anesthetics. When using the inhalation anesthetic vaporizer, the anesthesiologist can refer to the concentration of the drug in the exhaled breath. In contrast, with intravenous anesthetic infusion pumps, anesthesiologists often consider the infusion rate rather than the blood concentration. Therefore, today’s computer-controlled intravenous anesthetic infusion system, although relatively accurate and based on the theory of pharmacokinetics, is compared with the volatilization tank injecting inhaled anesthetics into the lungs and then indirectly entering the circulatory system, whether in theory or in practice. There are many shortcomings in the degree of convenience.

　　3. Computer-controlled drug infusion device as a reference to the concept of "vaporization tank for intravenous anesthetics"

　　1. For the infusion of intravenous anesthetics, TCI has made great progress in accordance with the concept of "vaporizer" due to the basic restrictions on the direct injection of the drug into the blood. The constant rate of infusion is used to maintain the continuity of the drug intake to maintain anesthesia and gradually reduce the infusion rate according to the pharmacodynamic characteristics of the drug to wake up in time. This is well known as the well-known BET infusion scheme (bolus, elimination, transfer). The determination of the drug infusion plan is determined by the initial blood concentration calculated by the TCI after the load and the distribution and clearance law of the drug after continuous infusion.

　　2. Using various BET schemes, TCI can calculate the expected blood drug concentration at each time point based on the pharmacokinetic parameters of the drug and the drug dose that has been infused. The real-time blood drug concentration expected by the computer enters the system as a feedback effect and constitutes the next drug infusion rate. TCI often changes the infusion rate every 10 seconds to keep the target plasma drug concentration constant.

　　3. The reasonable application of TCI in clinic requires anesthesiologist to master many aspects of knowledge. The change of TCI infusion rate is adjusted according to clinical experience and recommendations in anesthesiology literature. When an anesthesiologist applies TCI, he must input the patient’s age, weight and gender, and then determine the target concentration, and then calculate the infusion rate through TCI in order to obtain and maintain the blood concentration required for anesthesia. The successful application of TCI also depends on an in-depth understanding of the surgical process and surgical stimulation, as well as knowledge of the relevant physical and chemical properties and pharmacological characteristics of the infused anesthetics, such as effective therapeutic concentration.

　　4. The TCI drug infusion system designed based on the pharmacokinetic model theory has been described in detail in various anesthesia professional literature. From computer-assisted continuous infusion (CACI) to target-controlled infusion, and other computerized infusion devices designed based on the atrioventricular model theory, all are "open loop infusion" systems without patient feedback. The infusion is controlled mechanically. The current drug concentration predicted by the computer is only evaluated by the pump as a control signal. Therefore, the anesthesiologist must evaluate the patient's response in real time and adjust the required target concentration in time during the process of anesthesia.

　　5. The basic difference between computer-controlled open-loop infusion and closed-loop infusion is that the closed-loop infusion system can feedback the body's real-time response to the drug, such as muscle relaxation, heart rate, blood pressure, etc., in time, and change the drug according to this feedback effect. The infusion rate. For the open-loop infusion system, the setting point of the anesthesiologist is the target plasma or target effect chamber concentration; for the closed-loop infusion system, the setting point is the expected drug effect and the expected depth of anesthesia; during the closed-loop controlled infusion, feedback The effect is completed by monitoring facilities, such as peripheral nerve stimulators or EEG, BIS, etc. In contrast, for an open-loop infusion system, the feedback signal is the expected plasma drug concentration calculated according to the mathematical model of the compartment. For these two infusion methods, the rule of computer control is to consider the difference in the set point and feedback signal and the generated control signal. This control signal can change the pump command to obtain the desired set point.

　　4. New features of TCI software design

　　1. Smooth timing induction: The traditional TCI controller algorithm is based on the theory of BET. A single injection of a large dose makes the plasma concentration quickly reach a predetermined value, and then supplements the transfer volume and drug from the central chamber to the peripheral chamber Excretion. This infusion regimen will cause a larger initial loading dose, which will adversely affect patients with poor physical fitness and elderly patients. This TCI induction process is different from the uniform and slow bolus process commonly used in clinical practice. In order to solve this problem, some recent commercial target-controlled infusion systems use segmented induction technology. However, due to the limitation of the controller algorithm, it can only achieve the preset concentration through several jumps of concentration within a period of time. The new controller algorithm developed by Slgocontroler 3.10 has greater flexibility and breaks through the limitation that the initial plasma drug concentration must be achieved in the form of Blous. 　　

       2. Set logical limits for height and weight 　　

       3. Correction of population pharmacokinetic parameters 　　

       4. Built-in interface model of drug interaction and prompt of drug effect probability 　　

       5. Optimize the target concentration control infusion (OTCI) function 　　

       5. Challenges faced by TCI in the future development

　　Although open-loop TCI has made great progress towards the concept of "vaporization tank" for the infusion of intravenous anesthetics, it still faces many challenges. There is no doubt that these challenges are the same as those that have been encountered in the historical development of intravenous anesthetic infusion systems, such as accurate fluid infusion, accuracy of pharmacokinetics, and accuracy of pharmacodynamics.

　　　　1. Because the potent intravenous anesthetics used are dissolved or suspended in a small volume of liquid, the infusion pump must be able to inject the desired amount of solution accurately and in small amounts regardless of the open-loop or closed-loop infusion system. Modern micro pumps are under computer control. The infusion rate can be changed every 10 seconds at the fastest, and the infusion error is between 5-10%, which basically meets the requirements for the accuracy of the infusion pump. However, there are still many unresolved problems in the performance of the infusion pump. For example, what the computer needs is an infusion rate in seconds, while the existing infusion pumps still have not achieved a true constant continuous infusion in terms of mechanical performance, and the instantaneous flow error often accumulates over time. The closed-loop nerve blocker infusion system developed by Prof. Kern and his colleagues at the University of Utah is the only way to replace continuous infusion with a small loading dose. The theoretical advantage of this method is that it avoids pumping The instantaneous outflow rate error related to the start time. Within the acceptable infusion mode, time and error range, the ideal TCI system can determine and change the output rate according to the information provided by the feedback effect, so that it can reach and maintain the target effect chamber concentration and the desired drug effect to meet the surgical needs Claim. But looking forward to the development of bioengineering, the ideal infusion system still has many puzzles and challenges. 　　

             2. The operation of the optimal control system is quite complicated. The system must achieve several goals, some of which are completely hypothetical.

             (1) The control system must provide acceptable system performance including the induction time (that is, the time to reach the target concentration), the concentration and degree of overshoot, the time to reach the steady state, the degree of swing at steady state, the difference between the target concentration and the measured concentration. Maximum difference. 　　

             (2) The system must be able to make corresponding adjustments to the replacement of the syringe during the infusion or (such as the pump shutting off when the power is off) artificially interrupting the feedback signal. 　　

             (3) The control mechanism of TCI must also account for the non-equilibrium problem between the plasma and the effect chamber. Because the most relevant for drug effects is the drug concentration in the effect chamber or biological phase rather than the plasma drug concentration. Although the target concentration used by many TCIs is plasma drug concentration, the effect chamber concentration is more logical as the target concentration. When the plasma drug concentration is used as the target concentration, the action of many drugs will have a significant delay effect (that is, the plasma drug concentration significantly lags behind the drug concentration at the time of the effect). When the effect chamber concentration is used as the target concentration, the therapeutic concentration in the biological phase can be obtained quickly. 　　

             If there is no change in the course of a period of time, it can be imagined that the target plasma drug concentration can be accurately controlled. In fact, the effect chamber concentration (and the resulting degree of drug action) lags behind the plasma drug concentration, and the application of the target effect chamber concentration is closer to the time of drug action and parallel to the process of surgical stimulation. 　　

             3. Facing the challenge of engineering technology, a lot of experience has been invested in infusion technology, but there are many gaps of knowledge left in the field of clinical pharmacology that need to be filled. Modern pharmacokinetic-pharmacodynamic models are not sufficient to explain the significant variability in the body's treatment and response to drugs. 　　

             4. When using TIVA technology to combine different types of intravenous anesthetics or intravenous-inhalation combined anesthesia, the therapeutic window of different intravenous anesthetics and the best combination of drugs are still not accurately quantified. For example, if a 78-year-old male patient undergoes thoracotomy, oral midazolam is taken as a preoperative medication and then propofol is infused, what is the initial target concentration of sufentanil? For a 30-year-old male patient, intraspinal anesthesia During the downward hernia repair, how much is the target concentration of propofol set to achieve the goal of loss of consciousness and adequate sedation. Infusion techniques based on complex pharmacokinetic-pharmacodynamic models have made significant progress in filling these knowledge gaps. 　　

             5. At present, the biggest obstacle to the development of a fully automated target-controlled closed-loop infusion system is the lack of effective anesthesia depth monitoring equipment. Because a complete state of anesthesia is a compound effect, it includes loss of consciousness, intraoperative ignorance, (amnesia amnesia), perfect analgesia, complete muscle relaxation (motionlessness), reversibility, and selective inhibition. However, the current depth of anesthesia monitoring for these comprehensive functions is still a confusing "holy land, virgin land". Because the closed-loop infusion system requires meaningful pharmacodynamic feedback. For each component of a complete anesthesia state, although many feedback indicators such as four series of tests to monitor the degree of muscle relaxation, BIS to monitor the depth of sedation and the monitoring of various indicators of hemodynamics are very meaningful, but for the other Monitoring of components such as analgesia is still confusing. Especially when multiple drugs are used in combination, there is no indicator that can quantitatively analyze the overall anesthesia state.