TARGET CONTROLLED ANESTHESIA TACAN1
Luis Alberto Tafur B. MD. Eduardo Lema Florez. MD. SEGANEST. Clinica Visual y Auditiva Instituto Para Niùos Ciegos y Sordos del Valle del Cauca. Cali – Colombia seganest@seganest.com, luis.tafur@seganest.com
ABSTRACT Anesthesia with a controlled objective is an accepted growing technique among anesthesiologists worldwide. The paradigm on the need of technological resources of difficult achievement or the availability, in many hospitals and clinics of the world for its practice, has been replaced in some cases by the empirical administration of the medication. To date, there are multiple tools available that allow the administration of hypnotics and opioids pharmacokinetically through any institution without renouncing to the possibility of controlling in a precise manner the administration of the medication oriented towards reaching a probability of no response desired in accordance with the different stimulus or moments of an intervention.
Key Words.
TACAN, Target Controlled Anesthesia, Balanced Anesthesia, TIVA.
Objective
The main objective is to review the concepts of the use of a SAFE anesthesia, based on the TACAN model (Target Controlled Anesthesia), from the perspective of administering medication pharmacokinetically in adult patients.
TACAN (Target Controlled Anesthesia)
A characteristic of the anesthetic medications is that, unlike other medications, after administration it is possible to see the effect that we want in nearly real time. When we administer a medication to obtain a specific action, we can do so by following the various phases of administration of the same: the pharmaceutical phases, PK o PD2.
Pharmaceutically: This way, the main chemical of the medication and the way it is formulated is taken into account. We have some pre-determined doses to reach a therapeutic window.
Pharmacokinetically: This way, the changes the medication experiences in the body through absorption, distribution, metabolism and elimination, are taken into account. The goal is to maintain a constant, accurate and predictable concentration within a therapeutic window that ensures the desired effect.
Pharmacodynamically: The infusion of the medication is determined by the clinical response. Currently, in some anesthesiology journals, studies continue to be published where doses of propofol and remifentanil in mg/Kg are reported, without reporting the plasma concentrations used. This is an indicator that the paradigm of administering the drugs based on the art or the experience gained through the years persists. The following step of this evolution consists in reporting the plasma concentrations of medications that are administered. But the current concept is to take into account not only the Plasma Concentration of the medications, but their interactions, in other words, the probability of no response of the total of the different concentrations. Administering anesthesia is keeping in mind the Plasma Concentration that is being reached and the interactions among the drugs that are being administered. Rather than comparing the anesthesia with the flight of an aircraft, it is comparing the anesthesia with an air traffic controller, where you must:
1. Know in advance the probability of no response and the concentration target that will be required according to the type of surgery and time of the procedure. (Flight Plan).
2. Determine the concentrations of the different medications that are administered. (Location in space and time of the different aircraft).
3. Understand the interaction between the different medications to achieve a probability of no response. (Know the location of a plane with respect to the other)
Fig. 1. The concept of modern and safe Anesthesia not only implies knowing the plasma concentration of the medication, but how the plasma concentration influences the one from the other. In addition to a pilot, within the concept of safe anesthesia, the anesthesiologist is considered an air traffic controller, where he should have clarity regarding the interaction of the medication he is administering (flights), its plasma concentration (height) and its infusion (speed). In the concept of safe anesthesia, emphasis is made on the triad of the anesthesia: hypnotic component (yellow), analgesic component (blue) and muscle relaxant component (red); Trying to supply one of these components at the expense of high concentration in the others, contributes to a pharmacodynamics misbalance that can cause adverse effects. In the concept of safe anesthesia, using more than one medication with the same objective (two opioids, two hypnotics etc.), contributes in having more variables in the system (most flights) and consequently more risks. In the concept of safe anesthesia, the plan is to always keep the triad of the anesthesia with the less amount of medication at the appropriate concentration and always keeping their interactions in mind.
Concepts of Target Controlled Anesthesia – TACAN
Balanced anesthesia: Anesthetic technique that consists of the use of a combination of intravenous and inhalational agents for the induction and maintenance of general anesthesia3.
TIVA. The total intravenous anesthesia (TIVA) is a technique that uses only intravenous medications (i.v), for the anesthetic induction and maintenance, avoiding any type of inhalation anesthetic4.
Balance: According to the Royal Academy of the Spanish language, balance consists of "matching or putting in balance, counterbalance". According to the concept of balance, both in TIVA as Balanced Anesthesia, an assessment of the medication being administered is required. For this reason these terms lead to confusion and do not provide any real benefit to the objective of the administration of medication. The concept of Balanced Anesthesia is also applicable to TIVA since two balanced intravenous medications are used. However, when using an inhaled medication plus an intravenous, the concept of Balanced Anesthesia is not met at 100% since at some point of the anesthesia the concept of TIVA (induction) is used.
Target controlled Anesthesia (TACAN): TACAN is a technique for the administration of Anesthesia consisting of selecting, prior to its administration, the probability of no response desired in accordance to a determined stimulus (induction, maintenance and extubation) as well as the balanced plasma concentrations of the opioid and hypnotic required to achieve such probability. It is clear then, that the fundamental thing is to have a "flight plan": knowing the Plasma Concentration of the opioid and hypnotic medications with which a probability of no response and the ideal combination between these will be reached.
A flight plan must invariably include:
1. The concept of TACAN: With the revision of the model surface where you find all the possible combinations of opioid and hypnotic and the probability of no response expected of them, choose a desired PNR desired. It is imperative to know the pharmacodynamic interactions between the medications to be used.
2. Choose one of the combinations (isobolos) between appropriate hypnotic and opioid for the probability of no response selected (when the hypnotic is a halogenated inhalation anesthetics, the ET must be set for the age in accordance with Lerou nomogram which corresponds to the MAC required)
3. Keep in mind the PK variables of the medications to be used.
Pharmacokinetic variables:
In regard to the balance of the PK variables, in anesthesiology, there are two fundamental concepts that we have to keep in mind: The KE0 and the Contextsensitive half-life.
Concept of ke0.
When administering a medication, it does not produce its effect immediately on achieving its plasma concentration. There is a time delay called hysteresis 5. The explanation for this delay is that the action site of the drug is not in the plasma (V1), thus, the medication must pass from the plasma (V1) to the effect site (VE). This effect site is a very small virtual volume that is represented as a compartment that is located within the central compartment V1.
The time it takes for the medication to reach an equilibrium rate between the V1 and the effect site would be represented by the velocity constant K1e; the equilibrium constant between Ve and V1 would be the Ke1. Since Ve is a very small virtual volume, the K1e and the Ke1 do not represent any significant values, therefore it is decided to eliminate them and in their place, only the outflow is taken into account. This equilibrium constant is expressed as KeO or Ke0, which means it does not flow into another compartment. The concept of Ke0 was born with Galeazzi in the 80’s based on studies about the concentration of procainamide in the saliva and its importance lies in the fact that the KeO would represent how quickly the medication at the effect site inputs or outputs, therefore, the quicker it inputs (higher speed or greater KeO) the effect of the medication would be observed in less time. The T1/2 ke0 represents the time in which the concentration at the moment of effect reaches 50% of the Plasma Concentration when this is kept constant. In theory, when it reaches that concentration at the effect site, that is when the effects of the medication are seen.
T1/2 ke0 = log2 / ke0,
Ke0 = Lg2 / T1/2 ke0 = 0.693 / T1/2 ke0.
For practical effects, it can be considered that the Ke0 is the link between the PK phase and the PD phase and that a small Ke0 = long t1/2 Ke0 = major hysteresis. The concept of hysteresis, as we just mentioned, can be understood as the period of latency, which would be the time between the administration and the start of the pharmacological effect.
Context Sensitive Half-Life.
In the recovery from the effects of the drugs, it is necessary to predict the time that must pass for the concentration in the receiver to drop below the window at which the effect
occurs. When administered a single dose of a medication, it is sufficient to apply pharmacokinetic variables to the known behavior of the drug with which one can predict the time in which it reaches a concentration on the desired site and the time it was eliminated. However, when successive doses are repeated, that is to say, infusions, this prediction becomes complex and virtually impossible to calculate intuitively, thus making it necessary to use computer models to analyze the behavior of each of these doses in context with the other doses and with the duration of the infusion (context half-life). When a drug is instilled, patients recover before the half-life elimination. This phenomenon can be explained by the tricompartmental model, since suspending (in the central compartment) the administration of the drug, what was deposited in the peripheral containers (V2 - V3) returns to the central (V1), giving place to an extension in the t1/2 but without reaching the effective concentration by what the recovery of the clinical effects will be earlier because we are going to take more medication in V1 but less on the effector site. To explain this behavior as was the development of the concept of context sensitive half-life, which is defined as the time required for the Plasma Concentration of a drug that has been administered in infusion, decreases up to 50% after suspending it6,7. The concept of context sensitive half-time is also applicable to halogenated inhalation anesthetics8. As well as the administration of an intravenous medication through an infusion, the administration of the halogenated inhalation anesthetics is formed by an ongoing series of amounts of medication administered in the form of steam over a determined and variable period of time. This is, by definition, an infusion. The time it takes for the isoflurane, sevoflurane and desflurane, to decrease its plasma concentration by 50% after suspending their infusions is virtually the same, regardless of the time taken for the infusion and the MAC used9. If the concentration has been reached by the halogenated inhalation anesthetics at the time of its context half-life is below the MAC wake up, the patient will be awake five minutes after the infusion is suspended regardless of its duration10. If the concentration reached by the halogenated inhalation anesthetics at the time of its context half-life is above the MAC wake up, the patient will not yet be awake within five minutes of the suspension of the infusion, even when the plasma concentration has decreased by 50%. This explains why a difference
can and cannot be found at the wake-up time in accordance with the halogenated inhalation anesthetics used. When the elimination of the halogenated inhalation anesthetics required is 80%, the situation does not change for sevoflurane or for desflurane, but it does for isoflurane. After 50 minutes of infusion, the time required to eliminate the 80% of isoflurane is 10 minutes; for an infusion greater than 2 hours, the time necessary to eliminate the 80% of isoflurane is 30 minutes. When the elimination of the halogenated inhalation anesthetics required is 90%, the situation does not change for the desflurane, but it does for sevoflurane and isoflurane. The time of elimination of 90% of the sevoflurane increases from the minute 100 of administration reaching 60 minutes in infusions as long as 5 hours, being only slightly less than that of the isofluorano.
In summary, for prolonged infusions of halogenated inhalation anesthetics, there are no differences in the wake-up time when the MAC awakening is 50% of the scheduled infusion (as in anesthesia with Remifentanil with halogenated inhalation anesthetics, for example). When sevoflurane is administered for durations higher than two hours to more than 90% of MAC wake up (as in pure inhalation anesthesia), the wake up time may not differ much from that of a similar infusion with isoflurane. For desflurane, the time of elimination is independent from the concentration administered and the time, which is why in prolonged infusions, even in high concentrations, the time of elimination will be from five to seven minutes. For this reason, the desflurane would be the choice in balanced anesthesia with long-acting opioids, such as Fentanyl, which a fixed concentration of the opioid should be handled and in the few indications of pure inhalation anesthesia that are left, in which a MAC-BAR is required to reach
It is clear then that there are medications that have a rapid onset of action, others are slow, some slow context half-life and others rapid11,12. In the concept of TACAN, it is fundamental to seek equilibrium (balance) between these PK variables. Fig 2. If we organize the most commonly used anesthetic drugs according to their Pk profile, at the end of the spectrum, we would find the drugs with a high t1/2Ke0 (lower hysteresis:
DESFLURANE, REMIFENTANIL), others intermediate (SEVOFLURANE) and others low (greater hysteresis, slower onset of action: FENTANYL and ISOFLURANE). That is to say that balancing an opioid with halogenated inhalation anesthetics, it becomes logical to select two drugs that are complementary and that are at opposite ends of the spectrum because the use of drugs with similar profiles may be inefficient and wasteful of the benefit of one of the drugs. For example, using fentanyl with isoflurane (second circle), would be unwise, because the two are located on the same pole, sharing very similar PK characteristics, which would hinder the handling of a possible requirement of sudden or unplanned anesthetic depth change, or even the times with a different requirement within the same procedure, without affecting the course of the surgery and/or the wake up time of the patient. In the case of Remifentanil and Desflurane (first circle), they are located in the same polarity since they share very similar PK characteristics. Even when there is no doubt that there are few indications for this mixture, it is important to bear in mind that the awakening of the patient on some occasions can be very abrupt, associated with the use of analgesics, nausea and vomiting in the post anesthesia care unit may be greater13,14.
Fig. 2 Concept of TACAN to equilibrate (balance pharmacokinetic variables t1/2Ke0 and context sensitive half-time.
According to the PK characteristics of the propofol and fentanyl, its combination could be striking, if it weren’t given that the propofol lacks analgesic properties, all painful stimulus must be supplied by the fentanyl, which, due to its time of onset of action, it would be inopportune at the time of the management of a peak requirement during a surgery15.
In the schematic where you want to get a specific probability of no response and you choose the remifentanil plus a hypnotic; the concentration of the hypnotic usually remains static and the Remifentanil, due to its high Ke0 and its context sensitive halflife, it can be quickly adapted to supply the different moments of the intra-operative analgesic, since it would not be indicated to increase the hypnotic to manage painful spikes, except with the halogenated inhalation anesthetics, given that they have analgesic properties, taking into account that they are inferior to those of the Remifentanil.
For the fentanyl schematic of the plus a halogenated inhalation anesthetics hypnotic, if the KE0 of the same is taken into account, it is clear that its use should be directed toward a concentration high enough to include all the requirements of the different moments of an intervention, that is to say, suddenly changing its focus up or down is impossible, in addition to its context half-life, which would be altered with the repeated administration of bolos, which would cause a pharmacokinetic chaos and therefore would make the behavior of this medication unpredictable regarding the desired effects. It is logical then to suggest that when the fentanyl is selected, it must be planned with a fixed target concentration and the changes or different requirements during the surgery must be handled with halogenated inhalation anesthetics of an opposite profile, such as desflurane. In summary, given the pharmacokinetic profile of fentanyl16, it is necessary to consider that for a proper control of a probability of no response selected, it is better to have an infusion than a bolos implementation (Fig 3). In the second case, after a loading dose, during the first minutes of the Plasma Concentration, it will be greater than that found in the effect site and, after several minutes, the concentration at the effect site will be greater than the plasma. This is
avoided by administering a controlled infusion with the use of the nomogram of fentanyl by adjusting it in the time or, for the use of a single bolus in short surgeries, take into account the time it takes the fentanyl to reach and decrease the concentration at the effect site rather than in the plasma, since, as mentioned at the beginning of its administration, the Plasma Concentration will be greater than the Effect Concentration (EC) and as the time passes, due to its PK profile, the EC will remain above the Plasma Concentration for a few minutes.
Fig. 3. Left. Fentanyl Anesthesia + Halogenated inhalation anesthetics schematic: The concentration of fentanyl remains stable and the concentration of halogenated inhalation anesthetics varies depending on the requirements. Right: Remifentanil schematic + propofol or remifentanil + halogenated inhalation anesthetics. In both cases the hypnotic remains stable and the remifentanil changes according to the requirements of the procedure.
Based on the abovementioned, the first thing that must be done, is a planning in the equilibrated or balanced choice of the hypnotic and the opioid that allows the anesthesiologist to be able to leave a static variable and modify the other depending the need of the moment of the procedure. Fig 4.
Fig. 4 Equilibrated or balanced choice of the combination of medicines in accordance to the pharmacokinetic variables of the same. The concept of balancing starts from the selection of the drug to be administered.
Specific PK consideration for the halogenated inhalation anesthetics
All the anesthesiologists seem to have clear that the MAC of halogenated inhalation anesthetics relates in an inverse way with age. In spite of this, rarely does is the adjustment is carried out considering said variable. The cause can be the few practices that can result from the implementation of complex mathematical equations or regular use of simulators for the administration of halogenated inhalation anesthetics.
In 2004, Lerou published a simple graphical representation of the mathematical models (nomograms) to adjust the dose of halogenated inhalation anesthetics according to age17. In this nomogram, it is possible to select the exhale fraction of halogenated inhalation anesthetics necessary to obtain a desired MAC according to the age. In this way it is intended that the administration be as accurate as possible and avoid the waste of halogenated inhalation anesthetics and the expression of the undesirable effects of the same that occur as a result of the administration above the required dose or the intra-operative awakening or insufficient level that occurs with the administration of a sub therapeutic dose. With the availability of this simple instrument and with the possibility of monitoring in real time the ET of halogenated inhalation anesthetics, there
is no justification for the orientation of halogenated inhalation anesthetics empirically, based on the vital signs or opening and closing the steamer. Fig 5
Figure 5. Modified Lerou Nomogram. (Published 2004, BJA)
Probability of no response - Surface Model.
The simultaneous administration of the anesthetic drugs produces different PD interactions, which may be additive, synergistic or inhibitory.
The additive interactions (additive) are presented when two or more drugs with similar mechanisms of action are administered simultaneously, and the effect of such a combination is the same as what is expected by the simple sum of their effects; for instance, the lack of response to the incision can be achieved with a proposed target effect of propofol of 11 Âľg/ml at the effect site or with a MAC of 1.8 of sevoflurane, or
with a proposed target effect of 5.5 of propofol at the effect site plus a MAC of 0.9 of sevoflurane18.
The synergetic interactions occur when the drug combination produces a much greater effect than anticipated for the sum of the effects. For example, the probability of not response obtaining an answer before a stimulus would be achieved with a target propofol concentration of 10 mcg/ml or with a target remifentanil of 10 ng/ml; when we administer both drugs simultaneously, we could deduce that there would be a target of propofol 5 mcg/ml plus a target of remifentanil 5 ng/ml (additive interaction), but what is observed is that it requires a target of propofol of 2 mcg/ml plus a target of remifentanil 4 ng/ml for which there is no answer, this is what is known as synergistic interaction or "supra-additive"19.
The Antagonistic interaction occurs when the combination of the drugs produce a lower effect than expected for the sum of the effects. For example, the effective dose of 50 (DE50) for the inhibition of the postoperative pain is achieved with 5.8 mg of morphine or with 85 mg of tramadol, when we administer these drugs simultaneously, you would think that we would need 2.9 mg morphine plus 42.5 mg of tramadol (additive interaction), but what we see is that they still need 5.5 mg of morphine and 80 mg of tramadol for the inhibition of pain, this is an infra-additive interaction20. Fig 6.
Fig. 6. Possible interactions when two drugs are administered simultaneously.
When we graph a synergistic interaction, for example, in the vertical axis of the propofol and in the horizontal axis of the remifentanil, we obtain a curve that represents the desired effect in 50% (thick line) or in 95% (thin line) of the population. (Fig 7)
Figure 7. Isobologram of remifentanil and propofol. Probability of no response in 50% and in the 95%, before the stimulus of the intubation.
Each point of this curve (thin line) represents the possible combination (isobolo) between the Plasma Concentration and remifentanil propofol for no response to the stimulus, in this case the intubation21; R1P1 (5 ng/ml - 4.5 mcg/ml), R2P2 (7 ng/ml - 3.3 mcg/ml) and R3P3 (15 ng/ml - 1.8 mcg/ml). This curve represents the multiple isobolos for a Plasma Concentration to obtain the same effect, is what is known as an Isobologram.
The graphical representation in three dimensions of the different isobolograms, in which we can visualize the different probabilities of no response to the stimulation, with the respective Plasma Concentration, is what is known as surface model.
How do I interpret a Remifentanil - Propofol Surface Model?
A surface model is represented by a three dimensional graph wherein its axis "X" and "Y" are located the medicines with synergistic features and a few curved lines that represent the probability of no response in the patients. The probability of no response to the stimulus in 95% of the population is achieved with Plasma Concentration of remifentanil 7 ng/ml and propofol of 3 mcg/ml. (Thick Points). The probability of no response in 50% of the patients can be obtained with the following Plasma Concentration of remifentanil and propofol: (Figure 8) R1 and P1 = 2 ng/ml and 5 mcg/ml (circle) R2 and P2 = 4.5 ng/ml and 2.2 mcg/ml (square) R3 and P3 = 8 ng/ml and 1.5 mcg/ml (triangle).
Figure 8. Surface model that represents the different isobologramas between propofol and remifentanil. Amended of Mertens MJ te. Al. Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions. Anesthesiology. 2003.
This model has the characteristic, that while the concentration of remifentanil increases, the propofol concentration necessarily decreases, but not in an arbitrarily or randomly; each concentration of remifentanil corresponds to a certain concentration of propofol to reach the desired probability. The surface model consists of this; knowing the numeric value of the Plasma Concentration of propofol that corresponds to each Plasma Concentration of remifentanil, to predict the probability of no response in 50% or 95%. Based on this surface model, we can understand why to some extent, with different concentrations of remifentanil, determined by different infusions, we can get the same effect by adjusting, obviously, propofol concentrations. For that reason, some studies report concentrations of remifentanil for intubation of 5, 6 or 7ng/ml, all with satisfactory results. This information needs to be complemented with the Plasma Concentration used of the hypnotic to be able to interpret the results.
Another characteristic of this model is that, with high Plasma Concentration of propofol we can achieve the probability of no response in patients, whereas it is not possible with high concentrations of remifentanil. In other words, the remifentanil will always need hypnotic, while the hypnotic, according to its concentrations may not need remifentanil.
What if there are several options (R1P1, R2P2, R3P3 ‌) of combinations, which is the ideal?
If with this model we can infer the concentrations of each drug that we need to obtain a desired effect and in addition, see how with different concentrations we get the same effect, what then is the ideal concentration of each drug for optimum intra-operative anesthesia and allow the patient a quick recovery?
Vuyk, et al. designed a study wherein its aim was to identify the effective concentration 50 and 95 (CE50, CE95) at the effect site of propofol and the different opioids, with which an adequate anesthesia and a more rapid awakening will be ensured. The CE50 in the effect site of remifentanil and propofol after one hour of
infusion, were 4,78 ng/ml and 2,51 mcg/ml, respectively, with which the lowest time of awakening (6,1 minutes - Arrows, figure 22). The CE95 were 7.71 ng/ml and 2.70 mcg/ml, with a time of awakening of 9.4 minutes 22.
Figure 9. Ideal Relationship of Plasma Concentration between remifentanil and propofol, with which one obtains the probability of no response of 50% and once suspended the infusion of the patient acquire the awakening faster. Amended Vuyk J, et al. Propofol Anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology. 1997
How to interpret a Sevoflurane - Remifentanil surface model?
A surface model is represented by a three dimensional graph where in axis "X" and "Y" are located the medicines with synergistic features and some curved lines that represent the probability of no response in the patients23.
The probability of no response in 95% of the patients can be obtained the following plasma concentrations of remifentanil and volumes times a hundred of sevoflurane:
R1 and S1 = 6 ng/ml and 0.75 vol% (0.4 MAC in a 30-year-old patient, according to Lerou) R2 and S2 = 4 ng/ml and 1.2 vol% (0.6 MAC in a 30-year-old patient, according to Lerou) R3 and S3 = 11 ng/ml and 0.5 vol% (0.25 MAC in a 30-year-old patient, according to Lerou)
In figure 10, the probability of no response in 50% of the patients is represented by the purple curve of the graph, as well as the 95% probability, there are several combinations between the plasma concentrations of remifentanil and volumes times a hundred of sevoflurane to achieve the same result.
Fig. 10: Sevoflurane-Remifentanil Interaction Model
This model has the feature that while increasing the dose of remifentanil, it necessarily decreases the VOL% of sevoflurane, but, again, not in an arbitrarily or randomly; a particular VOL% of sevoflurane corresponds to each concentration of remifentanil to reach the desired probability. The surface model consists in this; knowing the numeric value of VOL% of sevoflurane that corresponds to each plasma concentration of remifentanil, to predict the probability of no response in 50% or 95%.
Another feature of this model is that with high VOL% of sevoflurane we can achieve the probability of no response in patients, whereas with high concentrations of remifentanil it is not possible; as is clearly seen in the graph where the curves can cross the axis of the "Y" but not the axis of the "X". In other words the remifentanil always needs sevoflurane, whereas sevoflurane, according to its concentrations, may not need the remifentanil to achieve a PNR. For example, it is possible to give only one anesthesia with sevoflurane (pure inhalation), but not with remifentanil alone.
What if there are several options (S1R1, S2R2, S3R3 ‌) of combinations, which is the ideal? If with this model we can infer the concentrations of each drug that we need to obtain a desired effect and in addition, see how with different concentrations we get the same effect, what then is the ideal concentration of each drug for optimum intra-operative anesthesia and allow the patient a quick recovery?
Manyam et al, designed a study whose objective was to identify the 95 effective concentration of sevoflurane and remifentanil, with which would ensure a no response to the stimulus and would allow the patient recover consciousness quicker once the administration of sevoflurane and remifentanil were suspended24 (Figure 11), finding that these correspond to 5 ng/ml and 1 V% (0.5 MAC for a 30-year-old patient, according to Lerou), approximately. In other words, the ideal concentration of sevoflurane for less time to wake up with a PNR95 in an infusion of 1 hour was the MAC awakening associated to a concentration of remifentanil of 5 ng/ml. Fig 11.
Fig. 11. Surface Model Remifentanil - Sevoflurane. PNR 95% Plasma Concentration Remifentanil 5 ng/ml + 1 ET of Sevoflurane. Modified Manyam. Anesthesiology 2006.
Remifentanil - Sevoflurane / Remifentanil – Propofol Surface Model.
Bearing in mind the two surface models, draws attention to the PNR 50 when using propofol and remifentanil is 4,78 ng/ml and 2,5 mcg/ml, respectively; and the PNR 95 when using remifentanil and sevoflurane is 5 ng/ml and 0,5 MAC respectively. Bearing in mind that the interactions between the propofol and the halogenated inhalation anesthetics are additives, it is expected that the PNR 50 of both combinations were similar, but what for propofol and remifentanil is the PNR 50 for remifentanil and sevoflurane is the PNR 95, why is this difference so vast?
At this point, clarity has to be made on the design of the study that was used for the realization of the surface model. For the remifentanil – propofol model, Vuyk proposed the PNR to the stimulus with a surgical abdominal incision. For the remifentanil sevoflurane model, Manyam proposed the PNR with the tetanic stimulation. It is clear
that the PNR from both studies were different and what was established by Vuyk was closer to reality. In our concept and by the pharmacodynamic interactions we believe that what Manyam called PNR 95 corresponds to a PNR 50, for the stimulus: surgical abdominal incision. While it is true that the halogenated inhalation anesthetics has analgesic properties and the propofol does not, in these models when two drugs are administered simultaneously, we no longer talk about medication A or B, but of a new molecule whose unit is capable of producing a PNR.
Pharmacodynamic interactions between halogenated inhalation anesthetic agents.
In the scheme of administration of anesthesia with remifentanil and propofol, the plasma concentration of propofol remains almost unchanged, around 2,5 mcg/mL and the concentration of remifentanil varies according to the type and/or time of the surgery.
In the case of remifentanil and halogenated inhalation anesthetics, the MAC of this remains almost unchanged (around 0,5) and the concentration of remifentanil is adjusted according to the type and/or time of the surgery. According to some studies, the awakening concentration of propofol is reached when you have concentrations of 1,6 mcg/mL, in the case of the sevoflurane, the awakening concentration is reached when you have a MAC of 0,325,26.
We could suggest that 0,5 MAC and halogenated inhalation anesthetics 2,5 mcg/mL dose of propofol are equipotent, as well as the concentration of awakening 0,3 MAC is equivalent to 1,5 mcg/mL; not far from the reality (Plasma Concentration awakening 1,6 mg/mL).
The validity of the deduction from the above data, it is confirmed by the work of Schumacher et al27 where the surface model of the propofol with sevoflurane is studied,
conclude that the interaction of these two drugs was additive for all the objectives that were proposed.
The results that they found were the following:
CE50 of propofol 3,68 mcg/ml = Ce 50 Sevoflurane 1,53 Vo% (0.76 MAC) CE50 of propofol 2,34 mcg/ml = Ce 50 Sevoflurane 1,03 Vo% (0.50 MAC) CE50 of propofol 5,34 mcg/ml = Ce 50 Sevoflurane 2,11 Vo% (1.05 MAC) CE50 of propofol 5,92 mcg/ml = Ce 50 Sevoflurane 2,55 Vo% (1.27 MAC) CE50 of propofol 6,50 mcg/ml = Ce 50 Sevoflurane 2,83 Vo% (1.41 MAC)
In all the cases (1 Vo%) 0,5 MAC of Sevoflurane was equivalent, approximately, a 2,5 mcg/mL of propofol.
In a surface model where the hypnotic remains stable and the variable that is changed is the concentration of remifentanil, when hypnotics have additive interactions, they are interchangeable pharmacodynamically and do not alter the model, as long as equipotent concentrations are used.
Eger E et al. in a study of additivity of 11 inhaled agents, found that all of the combinations that were done, were found to be additive with the exception of the combination of isoflurane with nitrous oxide, which proved to be an infraaditive combination. The research does not report a study with desflurane28.
In conclusion, the propofol as well as the Isoflurane, in a pharmacodynamic interaction model with sevoflurane, have an additive behavior, which make them extrapolated in a surface model, as long as an equipotent dose is used.
Planned No Response Probability
Before starting the anesthesia, you must have clarity on the PNR that is needed, during intubation, maintenance and awakening.
Considering that the intubation is a unique event in time, it requires you to have a PNR 95% at the time of anesthesia. Post-intubation should set a PNR 50% which may fluctuate according to the intra-surgical requirements. For extubation, a concentration of opioid without hypnotic is sufficient for a calm wake up, without coughing and with hemodynamic stability.
In chart number 1, the PNR 50 and 95 of the combination of Remifentanil-propofol, Remifentanil-halogenated
inhalation
anesthetic,
anesthetic has been summarized.
Chart 1. Probability of no response and concentrations of drugs.
Fentanyl-halogenated
inhalation
Sequence in the Target Controlled Anesthesia (TACAN)
Pharmacokinetic models have been available for decades. In spite of this, in the environment of the operating room there seems to be resistance to the adoption of new ways to administer medicines and one of the schematics most used
by
anesthesiologists may be as follows:
Example: this is the case of a 50-year-old patient scheduled for a surgery of the abdomen.
A. You select a rate of infusion in mg/Kg for the hypnotic B. You select a rate or opioid dose in mcg/kg. C. Eventually, you try to establish a plasma concentration for that dose of hypnotic D. A specific MAC for the halogenated inhalation anesthetic. E. Or the plasma concentration of the opioid. F. Without knowing it, they are already in a given probability of no response and probably achieve and maintain a hemodynamic stability. Figure 12.
Fig 12. Management Schematic of anesthesia without taking objectives into account.
Breaking paradigms.
Thinking about infusions before probabilities, is the first paradigm that blocks us at the time of administering controlled objective anesthesia. In the example above, a 50-yearold patient who will be performed an abdominal intervention, the first thing that we must ask ourselves is:
*What is the probability of no response that you want (A). For the case of the intubation, since it is a unique event in time, it is advisable to have a probability of no response (PNR) of 95 %. It is worth noting that while with the PNR 95 ensures that the 95% of the intubation will not require additional medications, a small percentage is going to have episodes of hypotension that can be handled easily. Think of a PNR 50 at the time of intubation, possibly ensure that the percentage of hypotension will be less but very probably some percentage of patients will have some degree of movement, a dramatic and unpleasant situation at induction.
*During the maintenance it is more physiological to handle a PNR 50 and adjust it according to the surgical requirement based on the vital signs and the BIS. It is worth noting that the vital signs are used to adjust a probability of no response and not as a basis for establishing infusions blindly.
*After having established the PNR 50 (A), we are looking for that plasma concentration of the opioid (B) in SYNERGY with the concentration of the hypnotic (C), are necessary to achieve the PNR 50.
*With this information and with the help of a TCI, a simulator or a nomogram, we set up the dose of the hypnotic (E) and the opioid (D) necessary to achieve said concentrations; finally with the doses found, we set the infusion required (F). Figure 13
Figure 13. Anesthesia schematic based on objectives.
Propose an administration of medicines from the infusion toward the probability of no response to the stimulus, is a paradigm that we must break to understand the concept of target controlled anesthesia TACAN (Target Controlled Anteshesia).
WHAT PROBABILITY OF NO RESPONSE DO I WANT?
INTUBATION 95% MAINTENANCE 50% AWAKENING 10%
WHAT PLASMA CONCENTRATIONS DO I NEED TO ACHIEVE THE DESIRED PNR?
PLASMA CONCENTRATION OF REMIFENTANIL? PLASMA CONCENTRATION OF PROPOFOL? HALOGENATED INHALATION ANESTHETICS MAC?
WHAT INFUSION IN mcg/Kg/h DO I NEED TO ACHIEVE THE PLASMA CONCENTRATION?
WHAT INFUSION IN "ET" DO I NEED TO REACH THE MAC?
Once established this schematic, choice of drugs, PNR and plasma concentration, the final step is to administer an infusion to achieve said desired concentrations, which can be set by nomograms, simulators or TCI systems.
Bibliography
1
TAFUR B, Luis Alberto, LEMA F, Eduardo. TACAN. ISBN 978-958-57844-2-0. Editorial Sociedad Colombiana de Anestesiología y Reanimación. Año 2013. 2
TAFUR, Luis Alberto and LEMA, Eduardo. Anestesia total intravenosa: de la farmacéutica a la farmacocinética. Rev. colomb. anestesiol. 2010;38(2):215-231. 3
Silver S. Balanced Anesthesia. J Am Dent Soc Anesthesiol. 1959;6(7):11.
4
JARMAN R. History of intravenous anaesthesia with ten years' experience in the use of pentothal sodium. Postgrad Med J. 1946;22(252):311-8. 5
Galeazzi RL, Benet LZ, Sheiner LB. Relationship between the pharmacokinetics and pharmaco- dynamics of procainamide. Clin Pharmacol Ther. 1976;20(3):278-89. 6
HughesMA,GlassPS,JacobsJR:Context-sensitivehalf-timeinmulticompartmentpharmaco- kinetic models for intravenous anesthetic drugs. Anesthesiology 1992; 76:334–41. 7
Youngs EJ, Shafer SL: Pharmacokinetic parameters relevant to recovery from opioids [pub- lished erratum appears in Anesthesiology 1995; 82:326]. Anesthesiology 1994; 81:833–42. 8
Hendrickx JF, De Wolf A. Special aspects of pharmacokinetics of inhalation anesthesia. Handb Exp Pharmacol. 2008;(182):159-86. 9
Biley M.J. Context sensitive half times and other decrement times of inhaled anesthetics. Anesth & Analg. 1997; 85:681-6.681 10
Bailey JM. Context-sensitive half-times and other decrement times of inhaled anesthetics. Anesth Analg. 1997;85(3):681-6. 11
Fred Roberts and Dan Freshwater-Turner Pharmacokinetics and anaesthesia Contin Educ Anaesth Crit Care Pain (2007) 7(1): 25-29 12
Graham SG. New drug in volatile anaesthesia--desflurane. Ann Acad Med Singapore. 1994;23(4):510-8.
13
Marana E, Russo A, Colicci S, Polidori L, Bevilacqua F, Viviani D, Di Stasio E. Desflurane versus sevoflurane: a comparison on stress response. Minerva Anestesiol. 2013;79(1):7-14. 14
Grundmann U, Silomon M, Bach F, Becker S, Bauer M, Larsen B, Kleinschmidt S. Recovery profile and side effects of remifentanil-based anaesthesia with desflurane or propofol for laparoscopic cholecystectomy. Acta Anaesthesiol Scand. 2001;45(3):320-6. 15
McClain DA, Hug CC Jr. Intravenous fentanyl kinetics. Clin Pharmacol Ther. 1980;28(1):106-14. PubMed
16 Tafur LA, Serna A, Lema E. Fentanilo PK/PD, un medicamento vigente. Rev. colomb. anestesiol. 2010;38:6883. 17 Lerou JG. Nomogram to estimate age-related MAC. Br J Anaesth. 2004;93(2):288-91. 18
Harris RS, Lazar O, Johansen JW, SebelPS. Interaction of propofol and sevoflurane on loss of consciousness and movement to skin incision during general anesthesia. Anesthesiology. 2006;104:1170-5. 19
Mertens MJ, Olofsen E, Engbers FH, Burm AG, Bovill JG, Vuyk J. Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions. Anesthesiology. 2003;99:347-59. 20
Mascoutah M, Mazoit JX, Benhamou D. The median effective dose of tramadol and morphine for postoperative patients: a study of interactions. Anesth Analg. 2005;100:469-74. 21
Johnson KB, Syroid ND, Gupta DK, Manyam SC, Egan TD, Huntington J, White JL, Tyler D, Westenskow DR. An evaluation of remifentanil propofol response surfaces for loss of responsiveness, loss of response to surrogates of painful stimuli and laryngoscopy in patients undergoing elective surgery. Anesth Analg. 2008;106(2):471-9, table of contents. 22
Vuyk J, Mertens MJ, Olofsen E, Burm AG, Bovill JG. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology. 1997;87(6):1549-62. 23
Botero LF, Bocanegra JC, Tafur LA. Anestesia Balanceada. 1st ed. Colombia. Corporaci贸n Integral de Servicios Scare; 2011. ISBN: 978-958-97432-5-6. 24
24. Manyam SC et al: Opioid- Volatile Anesthetic Synergy: A Response Surface Model with Remifentanil and Sevoflurane as Prototypes. Anesthesiology 2006; 105 (2): 267-78 25
Iwakiri H, Nagata O, Matsukawa T, Ozaki M, Sessler DI. Effect-site concentration of propofol for recovery of consciousness is virtually independent of fentanyl effect-site concentration. Anesth Analg. 2003;96(6):1651-5. 26
Katoh T, Suguro Y, Kimura T, Ikeda K. Cerebral awakening concentration of sevoflurane and isoflurane predicted during slow and fast alveolar washout. Anesth Analg. 1993;77(5):1012-7. 27
Schumacher PM, Dossche J, Mortier EP, Luginbuehl M, Bouillon TW, Struys MM. Response surface modeling of the interaction between propofol and sevoflurane. Anesthesiology. 2009 ;111(4):790-804. 28
Eger EI 2nd, Tang M, Liao M, Laster MJ, Solt K, Flood P, Jenkins A, Raines D, Hendrickx JF, Shafer SL, Yasumasa T, Sonner JM. Inhaled anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats. Anesth Analg. 2008;107(2):479-85.