Total intravenous anesthesia as a target-controlled infusion: an evolutive analysis

Abstracts

JUSTIFICATIVA E OBJETIVOS: A anestesia venosa total (AVT) sofreu diversos avanços desde o início da utilização da técnica. Desde a síntese dos primeiros anestésicos venosos, com a introdução dos barbitúricos (1921) e do tiopental (1934), a AVT evoluiu até o desenvolvimento da AVT com auxílio de bombas com infusão alvo-controlada (IAC). O primeiro modelo farmacocinético para uso em IAC foi descrito por Schwilden em 1981. Foi demonstrado, a partir daí, que era possível manter a concentração plasmática desejada de um fármaco utilizando-se bomba de infusão gerenciada por computador. CONTEÚDO: Este artigo visou a descrever as bases teóricas da IAC, a apresentar uma proposta de desenvolvimento de um vocabulário comum em IAC ainda não publicado no Brasil e a fazer uma análise crítica dos aspectos atuais da IAC no mundo e no Brasil. CONCLUSÕES: A chegada de novas bombas de infusão dotadas dos modelos farmacocinéticos do remifentanil, sufentanil e propofol inaugura outro capítulo da AVT e alinha o Brasil com a tendência mundial em IAC. Esses sistemas possibilitarão a IAC de hipnóticos e opióides concomitantemente. A conclusão mais importante, no entanto, refere-se à economia à medida que os fármacos utilizados nessas bombas não ficarão restritos apenas a uma empresa farmacêutica, a exemplo do que ocorreu com o propofol. Hoje já se dispõe de equipamentos para utilização de propofol e opióides, em IAC, que aceitam qualquer apresentação farmacêutica com a vantagem da possibilidade de alteração da concentração do fármaco na seringa, de acordo com a diluição desejada.

ANESTESIA, Geral

MISCELLANEOUS

Total intravenous anesthesia as a target-controlled infusion. An evolutive analysis

Anestesia venosa total en régimen de infusión objeto controlada. Un análisis evolutivo

Fernando Squeff Nora, TSA

Presidente da CE/TSA da SBA/2007

^{Correspondence to}

SUMMARY

BACKGROUND AND DOBJECTIVES: Total intravenous anesthesia (TIVA) has seen several developments since it was first used. Since the synthesis of the first intravenous anesthetics, with the introduction of barbiturates (1921) and thiopental (1934), TIVA has evolved until the development of TIVA with target-controlled infusion pumps (TCI). The first pharmacokinetic model for the use of TCI was described by Schwilden in 1981. From that moment on, it was demonstrated that it is possible to maintain the desired plasma concentration of a drug using an infusion pump managed by a computer.

CONTENTS: The objective of this report was to describe the theoretical bases of TCI, propose the development of a common TCI vocabulary, which has not been done in Brazil and make a critical analysis of the current aspects of TCI in the world and in Brazil.

CONCLUSIONS: The advent of new infusion pumps with pharmacokinetic models of remifentanil, sufentanil and propofol opens a new chapter in TIVA and aligns Brazil with the world tendency in TCI. Those systems will allow TCI of hypnotics and opioids concomitantly. However, the most important conclusion refers to the economy, since drugs used in those pumps will not be restricted to only one drug company, similar to what happened with propofol. Nowadays, TCI devices for the use of propofol and opioids, which accept any pharmaceutical presentation, with the advantage of changing the concentration of the drug in the syringe according to the dilution desired are available.

Key Words: ANESTHESIA, General: intravenous.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La anestesia venosa total (AVT) tuvo diversos avances desde el inicio de la utilización de la técnica. Desde la síntesis de los primeros anestésicos venosos, con la introducción de los barbitúricos (1921) y del tiopental (1934), la AVT evolucionó hasta el desarrollo de la AVT con el auxilio de bombas con infusión objeto controlada (IOC). El primer modelo farmacocinético descrito para uso en IOC, fue descrito por Schwilden en 1981. Quedó demostrado a partir de entonces, que era posible mantener la concentración plasmática deseada de un fármaco utilizando bomba de infusión por computador.

CONTENIDO: Este artigo quiso dejar sentadas las bases teóricas de la IOC, presentar una propuesta de desarrollo de un vocabulario común en IOC todavía no publicado en Brasil y hacer un análisis crítico de los aspectos actuales de la IOC en el mundo y en Brasil.

CONCLUSIONES: La llegada de nuevas bombas de infusión dotadas de los modelos farmacocinéticos del remifentanil, sufentanil y propofol inaugura otro capítulo de la AVT y coloca a Brasil a tono con la tendencia mundial en IOC. Esos sistemas facilitarán la IOC de hipnóticos y opioides concomitantemente. La conclusión más importante, sin embargo, se refiere a la economía en la medida en que los fármacos utilizados en esas bombas no quedarán restrictos a solamente una empresa farmacéutica, como por ejemplo lo que ocurrió con el propofol. Hoy ya disponemos de equipos para la utilización de propofol y opioides en IOC, que aceptan cualquier presentación farmacéutica con la ventaja de poder alterar la concentración del fármaco en la jeringuilla de acuerdo con la dilución que se desee.

INTRODUCTION

The concept of injecting drugs in the blood stream dates back to the mid XVII Century with Christopher Wren and Daniel Johann Major ¹. Wren dissolved opium in water and injected the solution in a dog. There are additional reports on similar experiments in which the dogs ran and urinated for several hours and at times died. In 1845 and 1853, the needle was invented by Francis Rynd and the syringe by Charles Gabriel Pravz ², respectively. Those essential tools opened the way for Pierre-Cyprien Oré who, in 1875, described 36 cases involving the intravenous use of chloral hydrate ³. This was the first report of intravenous anesthesia.

Since the synthesis of the first intravenous anesthetics, with the introduction of barbiturates in 1921 and thiopental in 1934, intravenous anesthesia has gone through several steps. At that time, pharmacological options and the knowledge of administration routes and systems, bioavailability, beginning and end of action, metabolism and excretion of intravenous drugs were scarce. Several drugs for intravenous administration have been synthesized since then and neuromuscular blockers and opioids (morphine was synthesized in 1803 by Serturner) ⁴ besides hypnotic agents like propofol (1970 – Glen), ethomidate (1974 – Doenicke) and midazolam (1976 – Fryer and Walser⁴) are among them. Propofol was used clinically in Europe for the first time in 1983 by Nigel Kay, in Oxford ^5-7.

The description of the pharmacological profile of intravenous drugs, whose studies started in 1950 with Brodie et al. in New York and with Kety in Philadelphia, formed the basis for the use of each one of those drugs ⁸.

In 1960, Price et al. described the physiological model of the distribution of thiopental⁹. This led to the first reports on the advantages of continuous intravenous administration of drugs when compared to bolus or intermittent bolus administration. The possibility to avoid fluctuations in plasma level of drugs is among those advantages ⁹.

In 1968, Bischoff and Dedrick elaborated a pharmacokinetic model, which included the concept that the influence of hepatic metabolism, flow between tissues and protein binding could cause important changes in the clinical result ¹⁰. The concept of non-compartmental model of Yamaoka et al. arose in 1978 ¹¹. In parallel to those new concepts, but especially after 1980 with the synthesis of propofol, studies aiming at the continuous administration of intravenous agents in anesthesia were initiated.

The concept of "compartmental effect", which stated that a drug acted on its biophase or in a specific location and not in the plasma where it was deposited, was described by Hull et al. in 1978 ¹². The first manuals on continuous infusion were developed as a consequence of those discoveries. One problem was still left to be solved, since the delineation of a proper infusion regimen depended on the knowledge of the resulting plasma concentration after administration of the drug. The observation that the onset of action of a drug administered in a peripheral vein presented a lag period generated the first obstacle to the continuous administration of intravenous drugs and led to the description of two concepts: distribution volume and steady state ¹². The solution proposed by Boyes et al. in 1970 was to administer an "attack" dose ¹³. Frequently, this initial dose resulted in extremely elevated plasma levels. In 1974, Wagner suggested a double infusion regimen ^14,15. It postulated the use of an initial dose and after a while the maintenance dose should be decreased. In 1969, Kruger-Thiemer had already proposed an infusion technique that used a bolus dose followed by a continuous infusion that varied gradually with time ¹⁶. This model was modified by several authors, until it was named 'BET" ^17-19, where "B" represented the bolus dose, "E" the amount of drug eliminated and "T" the amount of the drug transferred to other tissues. This scheme was even incorporated into some computer-assisted infusion pumps but, most of the time, it needed manual calculations done by the anesthesiologist.

A clinical assay by Ausems et al. in 1980 demonstrated for the first time that the need of alfentanil could vary among patients depending on the intensity and type of nociceptive stimulus ^20,21. The authors based their study on inhalational anesthesia, whose potency was determined by multiples of the MAC according to the stimulus to be blocked. This was a landmark for several other studies that tried to demonstrate that the need of drugs during surgeries could vary according to the intensity of the stimulus. White, Doze, Sear et al., among others, reported several studies demonstrating that the administration of anesthetics, intravenous or inhalational, in varying rates would be more advantageous than fixing only one rate of administration during the surgery ^22-26.

The first TIVA with propofol, in Brazil, date back to 1989, using infusion devices that need several calculations. The first results were conflicting and not reliable.

Measuring or inferring the final concentration of an intravenous drug in the plasma or in its site of action was a dream in Brazil and in the rest of the world, although, from 1981 on, it was already known that the action of the drug was at the effector site and not in the plasma, where the drug was deposited.

The first pharmacokinetic model for target-controlled infusion was described by Schwilden, in 1981. It was demonstrated that it was possible to maintain the desired plasma concentration of a drug using an infusion pump managed by a computer ²⁷. For such, the pharmacokinetic model of a drug already described and published was used. This led to the creation of the concept that generated the current definition of the expression Target-Controlled Infusion (TCI). It was after the implementation of the TIVA, with the help of devices that allowed TCI that, in 1991, Shafer and Varvel ²⁸ explained for the first time that the rate of decline of alfentanil, sufentanil and fentanyl at the effector site depended on the duration of the infusion. Through analysis of the recovery curves of those drugs they determined that there was a dependency on the decline of the concentrations and that this reduction was related with the length of time those drugs were administered for, besides the specific pharmacological characteristics of each one ²⁸. Thus, Hugues et al. described the term "context-sensitive half-life" to differentiate the end of action of a drug used in continuous infusion from that used in bolus ²⁹.

The objective of this report was to describe the theoretical basis of TCI, describe a proposal for the development of a common TCI vocabulary, which has not been done in Brazil and to make a critical analysis of the current aspects of TCI in the world and in Brazil.

CONCEPTS USED MORE OFTEN IN TCI

As TCI became more popular, several concepts were introduced. Thus, the ones used more often in TIVA with TCI will be described below.

According to the tricompartmental theory, the human body can be divided, for didactic purposes, in three separate compartments in which drugs are administered. Most authors have described the dispersion of a drug in the body based on this model. Concentration is one of the most important concepts in TIVA.

Concentration can be defined by the formula: Concentration = Dose or Mass / Volume.

To better understand the definition of concentration, just imagine a glass of water to which a solute, such as salt, is added. When salt is diluted in half a glass of water, the number of salt particles for each milliliter of water will be greater than the same amount of salt in a glass full of water. The amount of salt is called dose or mass. The number of particles per milliliter of water in the glass determines the concentration. The glass of water is analogue to the volume of the compartment, i.e., the volume that dilutes the drug administered. Since the drug is carried by the blood to each body compartment, the entry and exit flow of a drug for each compartment determines the concentration. Therefore, the places with greater cardiac output receive the drug faster. Brain, kidneys, liver, spleen, heart, lungs and endocrine glands are the first places to receive the drugs, and are known as compartment 1 or central compartment. From those places, drugs are distributed to the muscles, called compartment 2 and from those to the adipose tissue, called compartment 3. As the drug goes from one compartment to another, driven by differences in concentration, one can determine the transit constants between compartments.

When a certain dose, in mg.kg^-1 or µg.kg^-1, of a drug is administered in a peripheral vein the effect obtained is greater or smaller according to the volume diluting this mass of drug. A desired or undesired effect depends more on the final concentration of free drug than the dose administered initially.

When a drug is administered, a concentration is created during a determined period of time, generating an effect. When the effect is closely linked with the concentration, one can calculate the infusion regimen necessary to obtain a desired clinical effect and program it beforehand. For example, a plasma concentration of alfentanil of 475 ng.mL^-1 blocks the response to tracheal intubation in 50% of the cases (Cp50) ³⁰. This concentration can be achieved using a continuous infusion regimen calculated beforehand. Thus, the plasma concentration of alfentanil necessary to suppress the nociceptive response has been described for different types of surgeries. For breast, and low and upper abdominal surgeries, and return of spontaneous ventilation, the Cp50 of alfentanil described are 270, 309, 413, and 233 ng. mL^{-1 30}, respectively. The same is true for propofol and other opioids and the effects of the different concentrations are calculated and expected ^31,34-36. The technical limitation depends on the intensity of the stimulus generated by the manipulation of each surgeon, pharmacological distortion to maintain the expected concentration closed to the real measurement, changes in the volume of the central compartment, infusion pump error on delivering the drug and disconnection or loss of venous access.

BIOPHASE OR SITE OF ACTION

It is the site where the drugs exert their action, may they be desired or not. Those places usually include receptors with biological barriers determined by protein membranes. For this reason, most intravenous anesthetics are lipoproteins in order to cross those barriers faster to exert their actions. Therefore, there is a delay or latency between the initial administration of a drug and the initial effects. This occurs because the drug has to leave the plasma, where it is introduced through a peripheral vein, until it reaches the receptor molecule. This time will be greater with a decreased rate of passage of the drug from the plasma to the receptor. Therefore the term: Ke0.

Of all the speed rate variables between tow compartments, Ke0 is the most important, since it determines the rate that a drug leaves the central compartment, where it was administered and enters the compartment in which it exerts its effect.

The greater the Ke0, the higher the rate of entry of a drug in the action compartment. Consequently, the time needed for this to happen will be shorter. Thus, drugs with short T1/2 Ke0 have high Ke0 and fast onset of action.

Manipulating the value of Ke0 attributed to the pharmacokinetic model of a drug, it is possible to change the time of its onset of action. For example, when a TCI pump with a high Ke0 on the description of its model is used, the onset of action of the drug will be faster because this variable is used in the calculation of the bolus dose that the pump will administer. Consequently, this system will achieve faster induction, but it will use a higher dose of the drug. The probability of hypotension, when using this system with propofol, for example, will be higher. If the software that manages the model has a lower Ke0, the calculated bolus dose will be smaller and the induction slower, decreasing the intensity and probability of side effects, such as hypotension ³².

Most pharmacokinetic models of intravenous drugs describe a Ke0 within the limit of reasonability, i.e., something that offers rapid induction associated with the lowest incidence possible of side effects resulting from the calculated induction dose.

HYSTERESIS

Hysteresis is the time it takes a drug to achieve a balance between the plasma concentration and the effector site or biophase. By definition, the balance between the plasma compartment and the effector site, for intravenous drugs, corresponds to 4.32 half-lives of the drug. Thus, the product T1/2Ke0 ´ 4.32 corresponds to the equilibrium time between the plasma compartment and effector site. The hysteresis time of propofol, which is 2.4 minutes, can be calculated according to the T1/2Ke0 (equilibrium half-life). It means that the concentrations of propofol in the plasma and effector site will be in equilibrium, using a continuous infusion regimen, after approximately 12 minutes. An infusion pump with a propofol TCI management mechanism adjusted to maintain a plasma level of 4 µg.mL^-1 will achieve this same concentration at the effector site approximately 12 minutes after the beginning of the infusion. This time will be shorter for drugs with lower T1/2Ke0. For example, alfentanil and remifentanil have a T1/2Ke0 of only 1 minute. They are examples of opioids suitable for fast induction. A way of decreasing the equilibrium time between the plasma and the effector site is to increase the induction dose used in bolus when the infusion is initiated. Every TCI pump uses an initial calculation to administer the first dose. This dose is obtained by the product of the volume of distribution of the drug in the central compartment (Vdss) and the plasma target concentration chosen by the Anesthesiologist. Therefore, when the TCI of propofol is determined, with an initial target of 4 µg.mL^-1, the initial dose to be administered by the system will be 4 x Vdss of propofol, i.e., 4 x 17 or 20 = 68 to 80 µg.mL^-1. The Vdss of propofol varies, according to the model described, from 17 to 20 liters. The maintenance dose is established through more complex calculations ^33,37-39.

CENTRAL COMPARTMENT

Central compartment is the place the drug is deposited initially. It is responsible for the determination of the plasma concentration when a dose or mass of an anesthetic is used. The larger the central compartment, the lower the final concentration, as long as the same dose is maintained. The central compartment of children is larger than that of adults, and even greater than the elderly. This is the reason why higher doses are recommended for children when compared to adults and the elderly.

THIRD COMPARTMENT

The third compartment is responsible for the uptake of the anesthetic, usually liposoluble, since this compartment is represented by the adipose tissue. The third compartment is responsible for elevating the probability of drug accumulation after continuous infusion. Propofol has a high volume of distribution in the third compartment and a high tendency to accumulate during continuous infusion. This problem is minimized by its high metabolism rate. The ideal drug for continuous infusion must have, among other characteristics, a small volume in the third compartment.

CONTEXT-DEPENDENT HALF-LIFE

Context-dependent half-life determines the time needed for reduction in the plasma concentration of a drug to half of its concentration during the infusion once the administration is discontinued. From the equilibrium between the plasma concentration and at the effector site, it is possible to determine how long it will take a drug to reach half of the plasma concentration once the administration is interrupted. This concept is extremely important in TCI, since it makes that a system with several pharmacological parameters necessary for this calculation can infer the time of awakening or return of spontaneous ventilation, according to the calculated concentration at each moment. The limitations of this calculation vary directly with the margin of error of the model, since it does not measure plasma concentration directly, only infers this concentration based on mathematical calculations. Characteristics of the drug, of the patient, and association with other drugs can alter the clinical result observed or expected.

THERAPEUTIC WINDOW

Therapeutic window is the plasma concentration between Cp50 (plasma concentration in which the drug exerts its action in 50% of the cases) and Cp95 (plasma concentration in which the drug exerts its function in 95% of the cases). The concept of therapeutic window was introduced to explain that the dose of the drug administered, in anesthesiology, should not be too high, causing intense side effects, or too low, increasing the risk of not being enough to exert its action. It is the concept of Q.S.P. (quantum satis per), i.e., a drug should preferentially be administered at a dose that produces the desired effect, not more or less that. General anesthesia with hypnotics and opioids can be done with a wide variety of combinations, including: 1) elevated concentration of hypnotic + low concentration of opioid; 2) middle concentration of hypnotic and opioid (maximal synergistic effect between both drugs); and 3) low concentration of hypnotic + high concentration of opioid ⁴⁰. Several studies have described the therapeutic window of propofol in association with different opioids ^41,42. The pioneer was probably a study by Vuyk J et al. in 1997 that described the therapeutic window of propofol when it is associated with fentanyl, alfentanil, or sufentanil ⁴². The concentration of propofol, in µg.mL^-1, at the effector site described for the best recovery times when it was administered with fentanyl, or alfentanil, or sufentanil were 3.7, 3.5, and 3.3, respectively. The concentrations, in ng.mL^-1, of fentanyl, alfentanil and sufentanil were maintained at 2.1, 85 and 0.15, respectively ⁴².

Studies involving the use of propofol and remifentanil were done at a later date ^43,44. During abdominal surgery in patients receiving propofol and nitrous oxide associated with remifentanil, the blood concentration of remifentanil necessary to block the somatic response in 50% of the patients varied between 4.1 and 7.5 ng.mL^-1. Recovery occurred when the concentration of alfentanil reached 0.86 ng.mL^-1. But the ideal concentrations of propofol and remifentanil described by Vuyk J were 2.5 and 4.8 ng.mL^-1, respectively ⁴³.

TYPES OF INTRAVENOUS INFUSION OF DRUGS

Bolus

When a bolus dose of a drug is administered in a short period of time a concentration above that necessary to generate the desired effect is achieved. This is followed by a period during which the concentration declines rapidly until reaching plasma concentrations without clinical effect. The onset and end of action of a drug administered in bolus are equally fast. This occurs mainly by redistribution of the drug to body compartments where it does not have the desire effect. For example, a bolus dose of propofol of 2.5 mg.kg^-1 leads to a plasma concentration 4 to 5 times greater than necessary to induce hypnosis in adults. Several authors have described the concentration AT the effector site necessary to induce unconsciousness as varying between 1.1 and 4.7 µg.mL^-1. Side effects, like hypnosis, as a consequence of the initial overdose also appear rapidly. Thus, among the disadvantages of the administration of bolus doses of intravenous drugs, we could mention the increase in the incidence of side effects caused by the increased concentration. The administration of a bolus dose of a drug in the blood stream is followed by two distribution phases and one elimination phase. The distribution phases include the early and late, known as fast and slow elimination, respectively. The elimination phase is responsible for the depuration of the drug from the body and it depends on physiological processes of depuration, metabolism and excretion. Each elimination phase determines a half-life. Thus, 3 half-lives are described for intravenous drugs: half-life of fast and slow distribution and elimination half-life. Elimination half-life is calculated from the moment the metabolism of the drug is initiated on. Since the clinical effect depends on redistribution to other tissues that do not exert action, the correlation of elimination half-life with the time of action, observed in the daily practice, does not coincide with what is reported in the literature. Therefore, it is recommended the use of elimination half-life only for drugs used in a single dose or in bolus.

Continuous Infusion

When the drug is administered as a continuous infusion, a constant plasma concentration is achieved because, at the same time the drug is redistributed and metabolized, more drug is being administered and thus maintaining the desired plasma concentration or close to it. Continuous infusion of intravenous drugs can be done in one of two ways. First, with a manual infusion pump in which the doses are calculated by the anesthesiologist who regulates the pump as needed. Limitations of this technique include variations in plasma concentration and a tendency of the drug to accumulate, if the infusion is not changed, leading to less predictable results. The second uses an infusion pump with a TCI system. In this case, only the desired target concentration is informed to the pump, which, through a computerized system containing the pharmacokinetic model of the drug, controls the dose to be administered according to the changes in target informed by the anesthesiologist. Pharmacokinetic model is the description of the identity of the drug, since it is describes the rates of passage among body compartments, metabolism and Ke0, among other information. The main limitations of the technique include: the need to be familiarized with the plasma concentration and concentration at the effector site necessary for each drug, the margin of error of the pharmacokinetic model in the pump and the monopoly of companies that produce exclusive commercial presentations of the drugs.

Currently, TCI pumps are available for propofol (two models available: Marsh and Schnider), sufentanil and remifentanil that work with any commercial presentation of those drugs, besides allowing changes in their concentration according to the dilution preferred by the anesthesiologist.

CRITERIA FOR THE DESCRIPTION OF A PHARMACOKINETIC MODEL

Pharmacokinetic model is the description of the pharmacokinetic attributes of a drug. It is described according to a pharmacokinetic variable closely related with a clinical outcome as, for example, the relationship between Ke0 and onset of action. Behavior patterns of a drug in the human body are presented through those characteristics. If it has a fast Ke0, the onset of action will have the same behavior. Currently, according to Servin F et al, six criteria are recommended, which should be published, for a model to be considered reliable and thus able to be incorporated in a TCI for clinical use. Those criteria include: 1) criteria for the selection of the pharmacokinetic model; 2) criteria to define the patient population; 3) criteria to define a model and site of action; 4) criteria for the selection of the target-concentration to be used with each drug; 5) criteria to select the time to achieve the desired target-concentration; and 6) criteria to select the awakening concentration ⁴⁸. The pharmacokinetic behavior should be linear with the therapeutic band defined by doses approved for clinical use.

1. Criteria for the selection of the pharmacokinetic model

The model, adapted to represent a sample of the population (adult or pediatric), should be published in a renown journal. Ideally, the model should arise from studies representing the population (age, weight, gender, height, body mass index). It should be validated by specific studies of continuous intravenous infusion with acceptable performance indexes (bias < 30%), showing objective elements for maintenance of a certain target.

2. Criteria to define the patient population

Characteristics of the patients (age, weight, body mass index, height, and gender). Behavior of the infusion in patients with liver, kidney and cardiac failure. How TCI will behave with associated factors, such as pre-anesthetic medication, other drugs administered concomitantly and parallel treatments that might interfere (opioids, enzyme inhibitors or accelerators). Type of anesthetic applicability: determine the duration of the infusion and if it can be used in sedation and in intensive care units.

3. Criteria to define a model and site of action

Ke0 should be validated simultaneously with the corresponding pharmacokinetic model. Ke0 can be determined from a measurable pharmacodynamic effect of an anesthetic, such as the cortical electroencephalographic response (bispectral index, mean frequency, evoked potential, etc.). The pharmacokinetic model, along with the respective pharmacodynamic equivalence that has a Ke0 value, should be validated in studies of continuous infusion and in patient populations in which the models are being tested.

4. Criteria for the selection of the target-concentration

Concentration bands used should be established by studies done in several areas of anesthesia: Deep or superficial sedation with spontaneous or controlled ventilation, etc.; Type of patient: young, old, debilitated; type of surgery (variability of surgical stimuli); moment of the surgery: incision, intubation, skin closure, maintenance, sternotomy, peritoneal traction.

5. Criteria to select the time to achieve the desired target-concentration

The time necessary to achieve the desired target-concentration should be chosen according to the type of patient. Achievement of the target-concentration should allow gradual control so it can be obtained more slowly in the elderly and debilitated patients.

6. Criteria to select the awakening concentration

The awakening concentration should allow regulation of the infusion pump according to the values obtained by the mean population of published studies, taking into consideration the pharmacological interaction used in each one. Thus, it should be possible to change this value according to the behavior of each patient.

SAFETY MARGINS OF A PHARMACOKINETIC MODEL FOR TCI OF ANESTHETICS

To determine the safety of pharmacokinetic models incorporated in TCI pumps, several studies were undertaken ⁴⁹. In those studies, 3 variables were measured and reported: MDAPE – Median absolute performance error – represents the percentage of error between the expected concentration and the concentration measured in the plasma, MDPE – Median performance error – measures whether the concentration predicted by the infusion system is over- or underestimating the measured or real concentration, and the Wobble – measures whether the system is capable of maintaining the target concentration stable ⁴⁹. The ideal would be a MDAPE = 0, which means perfect performance. Currently, a model for TCI commercially available that has achieved this goal does not exist. Mean absolute error performance just informs if there is a tendency of the pharmacokinetic model to generate higher or lower concentrations than predicted, and it can be: -MDPE or +MDPE ⁴⁹.

Studies individualizing a model for each drug have been undertaken. With the TCI propofol pumps (use the pharmacokinetic model described by Marsh ⁵⁴), most studies indicate an error around 25% to 30% ^50-58. When other models of propofol in TCI were tested, the results were not as good. For the models described by Gepts ⁵², Tackley ⁴⁹, and Dyck ⁴⁹, the margins of error were 29%, 49%, and 20%, respectively. A new TCI model for propofol, described by Schnider et al., available in Brazil, has a performance error between 7% and 19% in adults ⁵⁰.

Target-controlled infusion models for sufentanil and remifentanil are available in Brazil. Several studies reported on the performance of both anesthetics in TCI using several pharmacokinetic models ^59,64.

For sufentanil, in adults ^60-62 and in some types of cardiac surgeries ^61,63, the mean error performance was between 11% and 30%, and for overweight patients, between 18% and 29%. Target-concentrations of sufentanil used more often, in cardiac surgeries, vary between 0.4 and 2 ng.mL^{-1 65}, while in non-cardiac surgeries they varied between 0.15 and 0.6 ng.mL^{-1 65}. Similarly, plasma concentrations around 0.2 ng.mL^-1 allowed return of spontaneous ventilation in most patients ⁶⁵.

For remifentanil, several studies have described an error performance of the model described by Minto ^66-68, which has varied from 18% to 37%. Recommended target-concentrations vary between 3 and 9 ng.mL^-1 and according to the intensity of the stimulus proposed.

CONCLUSIONS

Since the synthesis of the first drugs for intravenous use in anesthesia, when the knowledge was scarce and the anesthesiologist was a spectator, we went through several phases. Undoubtedly, the synthesis of propofol was a landmark in the development of TIVA with important concepts such as: effector site, compartmentalization of anesthesia components, concentration at the effector site and context-dependent half-life, all well established and ingrained on the daily routine of the anesthesiologist. Until the development of TCI, infusion pumps were manual and needed calculations and additional care during anesthesia. After the advent of TIVA with TCI several problems were solved, but others arose or persist. Although the margins of error of pharmacokinetic models incorporated in TCI pumps are accepted worldwide, they are still relatively high. The impossibility to measure directly the concentration of the drugs at the effector site represents another obstacle to be overcome, as well as the pharmacological variability of the drugs.

The arrival of the new infusion pumps with the pharmacokinetic models of remifentanil, sufentanil and propofol inaugurates another chapter on TIVA and aligns Brazil with the world tendency in TCI. Those systems allow the concomitant TCI of hypnotics and opioids. Nowadays, equipment for the use of propofol and opioids in TCI that use any pharmaceutical presentation with the advantage of allowing change in drug concentration in the syringe according to the desired dilution are available.

REFERENCES

Submitted em 26 de fevereiro de 2007

Accepted para publicação em 21 de dezembro de 2007

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Publication Dates

• Publication in this collection
  11 Mar 2008
• Date of issue
  Apr 2008

History

• Received
  26 Feb 2007
• Accepted
  21 Dec 2007