Clinical evaluation of two ke0 in the same pharmacokinetic propofol model: study on loss and recovery of consciousness

Abstracts

JUSTIFICATIVA E OBJETIVOS: A constante de equilíbrio entre o plasma e o sítio efetor (ke0) é utilizada pelos modelos farmacocinéticos para prever a concentração do fármaco em seu local de ação (Ce). Seria interessante que a Ce de propofol fosse semelhante na perda e na recuperação da consciência. O objetivo deste estudo foi avaliar o desempenho clínico de duas diferentes ke0 (rápida = 1,21 min-1 e lenta = 0,26 min-1) com relação à Ce durante a perda e a recuperação da consciência, usando o modelo farmacocinético de Marsh. MÉTODO: Participaram deste estudo 20 voluntários adultos sadios do sexo masculino. Em todos os voluntários, administrou-se propofol em regime de infusão alvo-controlada, modelo farmacocinético de Marsh ke0 rápida e, em outra oportunidade, usou-se o mesmo modelo farmacocinético com a ke0 lenta. Inicialmente, o propofol foi infundido em concentração-alvo plasmática de 3,0µg.mL-1. A perda de consciência e a recuperação de consciência basearam-se na resposta ao estímulo verbal. A Ce foi anotada no momento da perda e da recuperação da consciência. RESULTADOS: Na perda e na recuperação da consciência a Ce pela ke0 rápida foi diferente (3,64 ± 0,78 e 1,47 ± 0,29µg.mL-1, respectivamente, p < 0,0001), enquanto com a ke0 lenta a Ce foi semelhante (2,20 ± 0,70 e 2,13 ± 0,43µg.mL-1, respectivamente, p = 0,5425). CONCLUSÕES: Do ponto de vista clínico, a ke0 lenta (0,26 min-1) incorporada ao modelo farmacocinético de Marsh apresentou melhor desempenho que a ke0 rápida (1,21 min-1), uma vez que a concentração de propofol prevista em seu local de ação na perda e recuperação da consciência foi semelhante.

ANESTÉSICOS, Venoso; FARMACOLOGIA; EQUIPAMENTOS; Bomba de Infusão

JUSTIFICATIVA Y OBJETIVOS: La constante de equilibrio entre el plasma y el sitio efector (ke0), se usa por los modelos farmacocinéticos para prever la concentración del fármaco en su región de acción (Ce). Sería interesante que el Ce de propofol fuese similar en la pérdida y en la recuperación de la conciencia. El objetivo de este estudio, fue evaluar el desempeño clínico de dos diferentes ke0 (rápida = 1,21 min-1 y lenta = 0,26 min-1), con relación a la Ce durante la pérdida y la recuperación de la conciencia, usando el modelo farmacocinético de Marsh. MéTODO: Participaron en este estudio, 20 voluntarios adultos sanos del sexo masculino. A todos los voluntarios se les administró propofol en régimen de infusión objeto controlada, modelo farmacocinético de Marsh ke0 rápida y en otro momento, se usó el mismo modelo farmacocinético con a ke0 lenta. Inicialmente, el propofol se infundió en concentración-objeto plasmática de 3,0 µg.mL-1. La pérdida de la conciencia y la recuperación de la conciencia estuvieron basadas en la respuesta al estímulo verbal. La Ce fue anotada en el momento de la pérdida y de la recuperación de la conciencia. RESULTADOS: En la pérdida y en la recuperación de la conciencia, la Ce por la ke0 rápida, fue diferente (3,64 ± 0,78 y 1,47 ± 0,29 µg.mL-1, respectivamente, p < 0,0001), mientras que con la ke0 lenta la Ce fue parecida (2,20 ± 0,70 y 2,13 ± 0,43 µg.mL-1, respectivamente, p = 0,5425). CONCLUSIONES: Desde el punto de vista clínico, la ke0 lenta (0,26 min-1) incorporada al modelo farmacocinético de Marsh, presentó un mejor desempeño que la ke0 rápida (1,21 min-1), pues la concentración de propofol prevista en su región de acción en la pérdida y en la recuperación de la conciencia fue similar.

ANESTÉSICO, Venoso; propofol; COMPLICACIONES; despertar intraoperatorio

SCIENTIFIC ARTICLE

^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

Correspondence to

SUMMARY

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.

INTRODUCTION

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 T_½ke0 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; T_1/2ke0 = 2.60 min) was published¹³. However, there is little information in literature on the clinical performance of 1.21 min^-1 ke0 (fast ke0; T_1/2ke0 = 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.

METHODS

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.

RESULTS

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.

DISCUSSION

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 methodology^15-20, 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 authors^16,20.

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 propofol^31-34. 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 consciousness^31,34,35.

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 stimulation^32,37. 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.

REFERENCES

• 01. Kenny GN, White M - Intravenous propofol anaesthesia using a computerised infusion system. Anaesthesia, 1991;46:156-157.
• 02. Glen JB - The development of "Diprifusor: a TCI system for propofol. Anaesthesia, 1998;53(Suppl):13-21.
• 03. Marsh B, White M, Morton N et al. - Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth, 1991;67:41-48.
• 04. Vuyk J, Engbers FH, Lemmens HJ et al. - Phamacodynamics of propofol in female patients. Anesthesiology, 1992;77:3-9.
• 05. Smith C, McEwan AI, Jhaveri R et al. - The interaction of fentanyl on the Cp50 of propofol for loss os consciouness and skin incision. Anesthesiology, 1994;81:820-828.
• 06. Wakeling HG, Zimmerman JB, Howell S et al - Targeting effect compartment or central compartment concentration of propofol: what predicts loss of consciousness? Anesthesiology, 1999;90:92-97.
• 07. Struys M, Versichelen L, Rolly G - Influence of pre-anaesthetic medication on target propofol concentration using a "Diprifusor" TCI system during ambulatory surgery. Anaesthesia, 1998;53(Suppl 1):68-71.
• 08. Milne SE, Troy A, Irwin MG et al. - Relationship between bispectral index, auditory evoked potential index and effect-site EC50 for propofol at two clinical end-points. Br J Anaesth, 2003;90:127-131.
• 09. Doufas AG, Bakhshandeh M, Bjorksten AR et al. - Autometed responsiveness test (ART) predicts loss of consciousness and adverse physiologic responses during propofol conscious sedation. Anesthesiology, 2001;94:585-592.
• 10. Chortkoff BS, Eger EII, Crankshaw DP et al. - Concentrations of desflurane and propofol that suppress response to command in humans Anesth Analg, 1995;81:737-743.
• 11. Wessen A, Persson PM, Nilsson A et al. - Concentration-effect relationships of propofol after total intravenous anesthesia. Anesth Analg, 1993;77:1000-1007.
• 12. Nora FS - Anestesia venosa total em regime de infusão alvo-controlada: uma análise evolutiva. Rev Bras Anestesiol, 2008;58:179-192.
• 13. Iwakiri H, Nishihara N, Nagata O et al. - Individual effect-site concentrations of propofol are similar at loss of consciousness and at awakening. Anesth Analg, 2005;100:107-110.
• 14. Sheiner LB, Stanski DR, Vozeh S et al. - Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther, 1979;25:358-371.
• 15. Kenny GN - Ke0 of propofol evaluated with AEPex. Abstract World Congress Book, 1996.
• 16. Billard V, Gambus PL, Chamoun N et al. - A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect. Clin Pharm Ther, 1997;61:45-58.
• 17. Schnider TW, Minto CF, Gambus PL et al. - The influence of method of adminstration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology, 1998;88:1170-1182.
• 18. Schnider TW, Minto CF, Shafer SL et al. - The influence of age on propofol pharmacodynamic. Anesthesiology, 1999;90:1502-1516.
• 19. Struys MM, De Smet T, Depoorter B et al. - Comparison of plasma compartment versus two methods for effect compartment-controlled target-controlled infusion for propofol. Anesthesiology, 2000;92:399-406.
• 20. White M, Schenkels MJ, Engbers FHM et al. - Effect-site modelling of propofol using auditory evoked potentials. Br J Anaesth, 1999;82:333-339.
• 21. Struys MM, Coppens MJ, De Neve N et al. - Influence of administration rate on propofol plasma-effect site equilibration Anesthesiology, 2007;107:386-396.
• 22. Doufas AG, Bakhshandeh M, Bjorksten AR et al. - Induction speed is not a determinant of propofol phamacodynamics. Anesthesiology, 2004;101:1112-1121.
• 23. Barakat AR, Sutcliffe N, Schwab M - Effect site concentration during propofol TCI sedation: a comparison of sedation score with two pharmacokinetic models. Anaesthesia, 2007;62:661-666.
• 24. Nunes CS, Ferreira DA, Antunes L et al. - Individual effect-site concentrations of propofol at return of consciousness are related to the concentrations at loss of consciouness and age in neurosurgical patients. J Clin Anesth, 2009;21:3-8.
• 25. Sepúlveda P, Nunez G, Recart A - Induction TCI a sitio efector de propofol: evaluación clínica de dos diferentes ke0. Rev Argent Anestesiol, 2007;65:89-95.
• 26. Absalom AR, Mani V, De Smet T et al. - Pharmacokinetic models for propofol - defining and illuminating the devil in the detail. Br J Anesth, 2009;103:26-37.
• 27. Schuttler J, Ihmsen H - Population pharmacokinetics of propofol: a multicenter study. Anesthesiology, 2000;92:727-738.
• 28. Gan TJ, Glass PS, Sigl J et al. - Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology, 1999;90:1283-1287.
• 29. Kodaka M, Suzuki T, Maeyama A et al. - Gender differences between predicted and measured propofol Cp50 for loss of consciousness. J Clin Anesth, 2006;18:486-489.
• 30. White M, Kenny GNC, Schraag S - Use of target controlled infusion to derive age and gender covariates for propofol clearance. Clin Pharmacokinet, 2008;47:119-127.
• 31. Gajraj RJ, Doi M, Mantzaridis H et al. - Comparison of bispectral EEG analysis and auditory evoked potentials for monitoring depth of anaesthesia during propofol anaesthesia. Br J Anaesth, 1999;82:672-678.
• 32. Irwin MG, Hui TWC, Milne SE et al. - Propofol effective concentration 50 and its relationship to bispectral index. Anaesthesia, 2002;57:242-248.
• 33. Lysakowski C, Elia N, Czarnetzki C et al. - Bispectral and spectral entropy indices at propofol-induced loss of consciousness in young and elderly patients. Br J Anaesth, 2009;103:387-393.
• 34. Iannuzzi M, Iannuzzi E, Rossi F et al. - Relationship between bispectral index, electroencephalografic state entropy and effect-site EC50 for propofol at different clinical endpoints. Br J Anaesth, 2005;94:613-616.
• 35. Schraag S, Bothner U, Gajraj RJ et al. - The performance of electroencephalogram bispectral index and auditory evoked potential index to predict loss of consciousness during propofol infusion. Anesth Analg, 1999;89:1311-1315.
• 36. Pilge S, Zanner R, Schneider G et al. - Time delay of index calculation: analisys of cerebral state, bispestral and narcotrend indices. Anesthesiology, 2006;104:488-494.
• 37. Iwakiri H, Nagata O, Matsukawa T et al. - Effect-site concentration of propofol for recovery of consciouness is virtually independent of fentanyl effect-site concentration. Anesth Analg, 2003;96:1651-1655.
• 38. American Society of Anesthesiologists Task Force on Intraoperative Awareness - Practice advisory for intraoperative awareness and brain function monitoring. Anesthesiology, 2006;104:847-864.

Clinical evaluation of two ke0 in the same pharmacokinetic propofol model: study on loss and recovery of consciousness

Ricardo Francisco Simoni, TSA^I; Luis Otávio Esteves, TSA^II; Luiz Eduardo de Paula Gomes Miziara, TEA^III; Luiz Marciano Cangiani, TSA^IV; Gustavo Groth Oliveira Alves^V; André Luz Pereira Romano^V; Paula Úrica Hansen^V; Pedro Thadeu Galvão Vianna, TSA^VI

Publication Dates

• Publication in this collection
  26 Aug 2011
• Date of issue
  Aug 2011

History

• Received
  28 Nov 2010
• Accepted
  04 Jan 2011