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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.61 no.4 Campinas July/Aug. 2011
Ricardo Francisco Simoni, TSAI; Luis Otávio Esteves, TSAII; Luiz Eduardo de Paula Gomes Miziara, TEAIII; Luiz Marciano Cangiani, TSAIV; Gustavo Groth Oliveira AlvesV; André Luz Pereira RomanoV; Paula Úrica HansenV; Pedro Thadeu Galvão Vianna, TSAVI
IMaster's Degree in Anesthesiology from Faculdade de Medicina de Botucatu (UNESP); Co-responsible for the CET Instituto Penido Burnier; CMC
IICo-responsible for the CET Instituto Penido Burnier; CMC
IIIAnesthesiologist of Hospital Santa Sofia Ltda. and Fundação CMC
IVClinical Director of Fundação Centro Médico de Campinas; Co-responsible for the CET Instituto Penido Burnier; CMC
VR3 of Instituto Penido Burnier; CMC
VIPost-Doctorate at the Departamento de Anestesiologia da Universidade de Bristol; Professor of Departamento de Anestesiologia of Faculdade de Medicina de Botucatu da UNESP, Júlio de Mesquita Filho
BACKGROUND AND OBJECTIVE: The constant equilibrium between the plasma and effect site (ke0) is used by pharmacokinetic models to calculate a drug concentration in its site of action (Ce). It would be interesting if Ce of propofol was similar at loss and recovery of consciousness. The objective of this study was to evaluate the clinical performance of two different ke0 (fast = 1.21 min-1, and slow = 0.26 min-1) in relation to Ce during loss and recovery of consciousness using Marsh pharmacokinetic model.
METHODS: Twenty healthy adult male volunteers participated in this study. In all volunteers propofol was administered as target-controlled infusion, Marsh pharmacokinetic model for fast ke0 and, at a different time, the same pharmacokinetic model with slow ke0 was used. Initially, propofol was infused with a serum target-controlled infusion of 3.0 µg.mL-1. Loss of consciousness and recovery of consciousness were based on response to verbal stimulus. Ce was recorded at the moment of loss and recovery of consciousness.
RESULTS: On loss and recovery of consciousness, the Ce for fast ke0 was different (3.64 ± 0.78 and 1.47 ± 0.29 µg.mL-1, respectively, p < 0.0001), while with slow ke0 the Ce was similar (2.20 ± 0.70 and 2.14 ± 0.43 µg.mL-1, respectively, p = 0.5425).
CONCLUSIONS: Clinically, the slow ke0 (0.26 min-1) incorporated in the Marsh pharmacokinetic model showed better performance than the fast ke0 (1.21 min-1), since the calculated concentration of propofol at the effect site on loss and recovery of consciousness was similar.
Keywords: Pharmacokinetics; Propofol, administration and dosage; Intraoperative Awareness; Drug Delivery Systems.
The target-controlled system for propofol was developed by Kenny et al.1, but its commercial use started only in 19972. This system uses Marsh pharmacokinetic model, published on the same decade3.
The first generation of these systems only showed on its screen the target-dose and estimated plasma concentration (Cp). A delay in the relationship between Cp and clinical effect became evident. Several authors measured different plasma concentrations of propofol at the moment of loss and recovery of consciousness, with a wide variation between minimal and maximal values (0.8 to 5.4 µg.mL-1)4-11. This is basically caused by a delay in the balance between Cp and concentration of drug at its site of action located inside the central nervous system known as effect site6.
The equilibrium rate between plasma and effect site depends on several factors such as cardiac output, cerebral blood flow, and pharmacologic properties that determine the transference rate through the blood brain barrier (liposolubility and degree of ionization). The time of equilibrium between plasma concentration and effect site can be mathematically described as a first order constant, known as ke0.
In fact, the expression ke0 should be used to describe the rate of drug elimination from its effect site, but it has been estimated that the volume of effect site is insignificant, and, therefore, there is no need to separate the constant that enters and exits the site of action. Ke0 can be defined as the proportional variation of the concentration gradient between plasma and effect site in relation to the unit of time. In theory, the higher the value of Ke0, the higher the rate of entry of a drug at the site of action; therefore, the time taken for this to occur will be less. Thus, drugs with short T½ke0 have elevated ke0 and fast onset of action.
The value of ke0 is integrated in the target-controlled infusion allowing the insertion on the screen of the target-controlled infusion the estimated concentration of propofol in its effect site (Ce).
It has been recommended that the pharmacokinetic model with its pharmacodynamic equivalent that contains the values of ke0 should be validated in studies with continuous infusion and in patient populations in which the models are being tested12. All values of ke0 proposed are correct for the method used; however, they have little validation in clinical studies.
Currently, four target-controlled systems are commercialized in Brazil. The values of ke0 for propofol incorporated in these systems (Marsh model) can be 0.26 min-1 (slow ke0) or 1.21 min-1 (fast ke0).
An interesting way to assess these ke0 values proposed for propofol would be to observe the Ce at the moment of loss and recovery of consciousness. Although there is evidence that the concentration of propofol in its site of action (central nervous system - GABA receptor) is similar at the time of loss and recovery of consciousness, clinically this would allow an interesting individualized titration of the target dose of propofol reducing the possibility of intraoperative awakening episodes.
Recently, a study demonstrating a direct relationship between Ce on loss and recovery of consciousness with ke0 of 0.26 min-1 (slow ke0; T1/2ke0 = 2.60 min) was published13. However, there is little information in literature on the clinical performance of 1.21 min-1 ke0 (fast ke0; T1/2ke0 = 0.57 min).
The objective of the present study was to evaluate the clinical performance of two different ke0 (slow and fast) regarding the Ce of propofol during loss and recovery of consciousness using Marsh pharmacokinetic model3. The hypothesis tested was that the calculated Ce of propofol is similar for slow ke0 on loss and recovery of consciousness, which differ from that of fast ke0.
After approval by the Research Ethics Committee and signing of informed consent, 20 healthy adult male volunteers participated in this study. The sample size was based on a previous pilot study. Considering that the difference in proportionality between the calculated concentration of propofol at the site of action (Ce) with slow and fast ke0 (0.26 min-1 and 1.21 min-1, respectively) was 40% and the strength of analysis with an alpha error of 5% and beta error of 20%, it was demonstrated that 20 volunteers per group would be necessary.
Selected volunteers presented at a predetermined location after a 6-hour fasting period. All volunteers were monitored with electrocardiogram for heart rate (HR) (DII and V1 derivations), peripheral oxygen saturation (SpO2), non-invasive mean arterial pressure (MAP), and bispectral index (BIS). Oxygen under nasal catheter, 2.0 L.min-1, was administered; the left antecubital vein was punctured and connected to a venous catheter with propofol (Propovan® - Cristália Produtos Químicos e Farmacêuticos Ltda.). Saline infusion to replace the fasting period or insensible losses was not used.
Propofol was administered as target-controlled infusion using Marsh pharmacokinetic model, slow ke0, and, at a latter opportunity, using the same pharmacokinetic model with a fast ke0. An infusion pump (Anesthesia Pilot II® - Fresenius-Kabi) coupled to the infusion management (ANESTFUSOR® - University of Chile, Santiago) was used (Figure 1). The administration sequence of propofol was randomized and computer generated.
Initially, propofol was infused as a target-plasma concentration of 3 µg.mL-1, based on a previous study13. The loss of consciousness (LOC) was defined as loss of response to verbal stimulus (calling the volunteer by his name using a normal tone of voice). This verbal stimulus was repeated three times at 30-second interval by another investigator who was unaware of the calculated concentration at the site of action (Ce).
If loss of consciousness did not occur after the equilibrium of Ce and Cp at 3.0 µg.mL-1, Cp was increased by 0.5 µg.mL-1, and so forth, until the volunteer could not respond to the verbal stimulus. After loss of consciousness, target-controlled infusion was maintained for 15 minutes. After this period, Cp was decreased to zero until recovery of consciousness (ROC) was observed, defined as response to a verbal stimulus (calling the volunteer by his name using a normal tone). This stimulus was repeated three times at 30-second intervals by another investigator who was unaware of the calculated Ce. This methodology was similar to that of a prior study13.
The calculated concentration at the site of action and BIS were recorded whenever the volunteer lost and recovered his consciousness. The maximum and minimum BIS during infusion and the dose of propofol were also recorded.
Paired Student t test was used in the statistical analysis of parametric parameters and results were expressed as mean and standard deviation. Non-parametric parameters were analyzed by Wilcoxon test for paired samples and the results expressed as median. A p lower than 0.05 was considered statistically significant.
The age, weight, height, and mean body mass index of volunteers are presented in Table I. The mean Ce calculated for the fast ke0 on loss and recovery of consciousness was different (3.64 ± 0.78 and 1.47 ± 0.29 µg.mL-1, p < 0.0001), while with slow ke0 the calculated mean Ce was similar (2.20 ± 0.70 and 2.13 ± 0.43 µg.mL-1, respectively, p = 0.5425) (Figures 2 and 3).
A correlation between the calculated concentration of propofol in its site of action on loss and recovery of consciousness with slow and fast ke0 (p = 0.0249 and p = 0.0023, respectively) was observed (Figures 4 and 5).
The variation in MAP, HR, and SpO2 at the initial period and at 5, 10, and 15 minutes after loss of consciousness, and the initial BIS on loss and recovery of consciousness with the minimum and maximum values during infusion, can be seen in Tables II and III.
Time until loss and recovery of consciousness, dose of propofol used, time of propofol infusion, and mean target-plasma dose achieved with fast and slow ke0 are in Table IV.
Significant respiratory depression (SP < 92%) or any other adverse event was not observed during the study. The use of Guedel airway or any other instrument to maintain patent airways was not necessary.
The objective of the preset study was to evaluate the performance of two equilibrium constants (ke0 = 1.21 min-1 and ke0 = 0.26 min-1) incorporated in the Marsh pharmacokinetic model in relation to the Ce of propofol on loss and recovery of consciousness, assessed by the response to a predefined auditory stimulus.
The first study to determine the ke0 was published by Sheiner et al.14 in 1979 using a neuromuscular blocker (d-tubocurarine) where it is possible to objectively evaluate its effects. However, to date there is no direct method to estimate the concentration of intravenous anesthetics at the site of action. But the value of ke0 can be estimated by indirect methods, non-parametrically (based on blood samples), or parametrically (based on plasma concentration calculated by a pharmacokinetic model).
There is no consensus in literature on the ideal method to obtain the value of ke0 for propofol. Thus, as a consequence of the current methodology15-20, there is a large variability among proposed values (between 0.20 and 1.21 min-1). This difference has a partial relationship with the infusion rate of propofol used. By using electroencephalogram, it has been demonstrated that the equilibrium of propofol in its site of action is faster after a bolus injection than with a continuous infusion21. However, with rates up to 60 mg.min-1 a difference in the value of ke0 was not observed22.
The use of a single infusion pump attached to the infusion management program (ANESTFUSOR), in which the ke0 in the same Marsh model varies, eliminated the bias of using two infusion systems with different accuracies.
When the Ce of propofol was correlated with the degree of sedation (OAAS) using BIS values, a better performance was observed with the original Marsh model (ke0 = 0.26 min-1) when compared to the Schnider model (ke0 = 0.45 min-1)23, since while the concentration of propofol on its site of action calculated by the Marsh model increased, the degree of sedation also increased and BIS decreased proportionally. The inverse relationship was also observed.
The results of the present study indicate that by the method used the slow ke0 (0.26 min-1) had a better performance, since the Ce of propofol at loss and recovery of consciousness was similar (2.20 and 2.13 µg.mL-1, respectively). This result was similar to that of other authors who used the same method13, although there is no evidence that this is actually occurring within the central nervous system.
Despite the great difference observed between the Ce at loss and recovery of consciousness (3.64 and 1.47 µg.mL-1, respectively) with the fast ke0 there was a positive correlation. This correlation was also observed in another study that evaluated the loss and recovery of consciousness according to the same criteria24. Other authors have alerted about the non-linearity found between the Ce of propofol by fast ke0 and anesthesia induction, highlighting a greater reliability of slow ke0 as a titration guide25.
Slow ke0 (0.26 min-1) was first used on first generation IAC systems to estimate the effective concentration, which was always associated with the Marsh model. This value was extracted by using auditory evoked potentials (AEPex), but the details of this method are unknown, since this study was published only as a summary15. This value of ke0 is very similar to the 0.20 min-1 proposed by other authors16,20.
The fast ke0 (1.21 min-1) was suggested later by Struys et al.19, using the time to peak effect (TTPE) and BIS. After a bolus dose, the maximum clinical effect will occur when concentration on the site of action reaches its maximal level. Time to peak effect is defined as the time interval between the end of the bolus injection and peak clinical effect. This time is not dependent on the size of bolus. Using a fast ke0 with the Marsh model, the TTPE was approximately 1.6 minutes, which is similar to the result reported by another study17. Obtaining a result outside the equilibrium phase of propofol represents a disadvantage of this method26, making it difficult to observe a single maximal effect in a real clinical situation due to several factors such as signal interference (BIS),.
The amount of propofol used was significantly greater with the fast ke0 than with slow ke0. This was translated into lower BIS values during infusion and consequently longer awakening time with fast ke0. This can be explained by the fact that when the ke0 of 1.21 min-1 was used, many volunteers did not lose consciousness after the fast initial equilibrium of Ce and Cp at 3.0 µg.mL, which required a gradual increase in Cp until loss of consciousness. Therefore, with fast ke0, mean Cp during the assay was greater than the Cp of volunteers with slow ke0 (3.8 and 3.1 µg.mL-1, respectively).
Despite the greater amount of propofol used with fast ke0, significant hemodynamic repercussions were not observed, as the mean reduction in MAP was no more than 20%, while the HR remained stable during the study. Similar values were obtained with slow ke0. In only one moment (15 minutes after loss of consciousness) the HR was significantly different between groups.
Gender is an important variable in the pharmacokinetic of propofol27. A study has demonstrated that female patients recover faster after anesthesia with propofol, alfentanil, and nitrous oxide28. The calculated plasma concentration in females tends to be overestimated29. Recently, it has been demonstrated that there is the need to correct the depuration and volume of the central compartment of propofol according to gender and age to improve the previsibility of the Marsh model 30. To decrease bias, this study was conducted with the same gender (males) and within the same age range (young adults).
The better performance with slow ke0 might be partly explained by the method used in the present study of evaluating loss and recovery of consciousness. Most likely, the proposed auditory stimulus had better correlation with the evoked auditory potential (AEPex) than with BIS. Note that the AEPex was the tool used to extract the value of ke0 in the original Marsh model15.
It has been demonstrated in literature that the auditory evoked potential index (AEP index), BIS, and entropy have a positive correlation with the Ce of propofol31-34. They are all able to assess the degree of sedation and separate the state of being awake from being anesthetized. However, studies have demonstrated that the AEP index and entropy are more accurate in distinguishing the transition from the individual condition of unconsciousness to the state of consciousness31,34,35.
In the present study BIS values were statistically different at loss and recovery of consciousness in both ke0 investigated. This difference could be explained by a delay in processing the BIS signal, and the value seen on the screen refers to a previous moment. This delay can vary from 5 to 60 seconds according to the context and its changing tendencies36. However, intergroup results were similar (Table III).
Limiting factors of this study include the type of model used and the lack of measurements of the plasma concentration of propofol. The model with volunteers did not resemble a real surgical situation as the volunteers only received an auditory stimulus. It is known that the Ce of propofol necessary for loss of consciousness is greater in the presence of pain or surgical stimulation32,37. Thus, this model simulates only procedures with little nociceptive stimulus or in case of painful stimulus is blocked by regional anesthesia. The lack of measurement of plasma propofol concentration did not allow a more detailed interpretation of the results.
Recently, the task force of the American Society of Anesthesiologists included total intravenous anesthesia as a risk factor for intraoperative awakening38. Note that in the United States the target-controlled infusion was not approved by the FDA for clinical use. As demonstrated in another study13, conducting total intravenous anesthesia with propofol based in populational means (Cp50 or Ce50) can predispose the patient to intraoperative awakening and to retain memory of the procedure, since there is a wide pharmacodynamic variability. Even with slow ke0, which showed similar Ce of propofol at loss and recovery of consciousness, the variation of Ce at loss of consciousness was from 1.0 to 3.6 µg.mL-1, while with the fast ke0, this variation ranged from 2.3 to 5.9 µg.mL-1. Note that the present study was undertaken with a very homogenous group of volunteers.
In agreement with other authors33, we suggest that to reduce the incidence of intraoperative awakening slow ke0 associated with the Marsh model and titration of the maintenance target dose based on the calculated dose-effect for loss of consciousness should be used. Most likely, this target dose will need small adjustments to correct the inherent mathematical error of the pharmacokinetic model, and in situations in which the nociceptive stimulus is not completely blocked.
Corroborating the initial hypothesis, we conclude that the slow ke0 (0.26 min-1) incorporated in the Marsh pharmacodynamic model showed better clinical performance than the fast ke0 (1.21 min-1), as the calculated effect concentration at loss and recovery of consciousness was similar, although there is no evidence that this actually occurs in the central nervous system.
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Correspondence to: Submitted on November 28, 2010. Received from the CET Instituto Penido Burnier and Centro Médico de Campinas (CMC), Departamento de Anestesiologia da Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP), Brazil.
Dr. Ricardo Francisco Simoni
Rua Alzira de Aguiar Aranha, 552
13084768 - Campinas, SP, Brazil
Approved on January 04, 2011.
Submitted on November 28, 2010.
Received from the CET Instituto Penido Burnier and Centro Médico de Campinas (CMC), Departamento de Anestesiologia da Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP), Brazil.