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Rev. Bras. Anestesiol. vol.52 no.3 Campinas May/June 2002
Simplified method to maintain propofol blood concentration in an approximately constant level associated to nitrous oxide in pediatric patients *
Método simplificado para manutención de la concentración sanguínea de propofol en nivel aproximadamente constante, asociado al óxido nitroso en el paciente pediátrico
Pedro Thadeu Galvão Vianna, TSA, M.D.I; Elizabeth Pricoli Vilela, M.D.II; Francisco Carlos Obata Cordon, M.D.II; Lídia Raquel de Carvalho, M.D.III
IProfessor Titular do CET/SBA do Departamento
de Anestesiologia da FMB UNESP
IIME do CET/SBA da FMB UNESP
IIIProfessora Assistente Doutora do Departamento de Bioestatística do Instituto de Biociências da FMB UNESP
BACKGROUND AND OBJECTIVES: Maintaining
target-controlled propofol blood concentrations in approximately constant levels
is a technique that can be used in a simple way in the operating room. The aim
of this study was to compare in clinical and laboratorial terms propofol infusion
in children, using Shorts and Marshs pharmacokinetic parameters.
METHODS: Forty-one patients of both genders, aged 4 to 12 years, physical status ASAI or ASAII were distributed in two groups: Group S (n = 20) and Group M (n = 21). Shorts pharmacokinetic parameters were applied to group S, while Marshs pharmacokinetic parameters were applied to group M. Intravenous anesthesia was induced with 30 µg.kg-1 bolus alfentanil, 3 mg.kg-1 propofol and 0.08 mg.kg-1 pancuronium. Patients were intubated and anesthesia was maintained with N2O/O2 (60%) in controlled mechanical ventilation. Propofol infusion in group S was 254 µg.kg-1 (30 min) followed by 216 µg.kg-1.min-1 for additional 30 minutes. Propofol infusion in group M was 208 µg.kg-1 (30 min.) followed by 170 µg.kg-1.min-1 for additional 30 minutes. Using specific pharmacokinetic parameters for each group, the goal was a target-concentration of 4 µg.kg-1 propofol. Three blood samples were collected (at 20, 40 and 60 minutes) to measure propofol by the High Performance Liquid Chromatography method.
RESULTS: Groups S and M were similar in age, height, weight and gender (p > 0.05). There were no statistically significant differences between groups in SBP, DBP, HR, FiN2O, hemoglobin SpO2 and end tidal PETCO2. The number of repeated alfentanil boluses showed no statistically significant difference between both groups. Bispectral index (BIS) showed also no statistically significant differences between M0 (awaken) and remaining moments in both groups. Error Performance Median (EPM) and Error Performance Absolute Median (EPAM) values were statistically different between groups in moment 60. Median propofol blood concentrations (µg.kg-1) were significantly different between groups M and S in moment 60 and between moments 40 and 60 in group S.
CONCLUSIONS: Anesthesia with propofol using Marshs pharmacokinetic parameters (group M) showed a lower error rate for obtaining 4 µg.kg-1 propofol target-concentration. In addition, less propofol was needed to obtain similar clinical results. For these reasons, it should be the method of choice for children ASA I aged 4 to 12 years.
Key words: ANESTHETICS: Gaseous: nitrous oxide; ANESTHETIC TECHNIQUES, Venous: intravenous anesthesia; HYPNOTICS: propofol
JUSTIFICATIVA Y OBJETIVOS: La manutención
de concentración sanguínea alvo-controlada en niveles aproximadamente
constantes del propofol es una técnica que puede ser empleada de modo simplificado
en la sala de cirugía. La finalidad de esta pesquisa es comparar clínica
y laboratorialmente la infusión de propofol en niños usando los atributos
farmacocinéticos de Short y de Marsh.
MÉTODO: Fueron estudiados 41 pacientes con edades entre 4 y 12 años, de ambos sexos, estado físico ASA I ó II, distribuidos en dos grupos S (20 pacientes) y M (21 pacientes). En el Grupo S se utilizaron los atributos farmacocinéticos de Short, y en el Grupo M, los atributos farmacocinéticos de Marsh. La inducción anestésica fue hecha con bolus de alfentanil 30 µg.kg-1, propofol 3 mg.kg-1 y pancuronio, 0,08 mg.kg-1 por vía venosa. Se procedió a intubación traqueal y a manutención con N2O/O2 (60%) en ventilación controlada mecánica. En el grupo S la infusión de propofol fue de 254 (30 min) seguido de 216 µg.kg-1.min-1 por más 30 min. En el grupo M la infusión de propofol fue de 208 (30 min) seguido de 170 µg.kg-1.min-1 por más 30 min. A través del atributo farmacocinético específico a cada grupo la meta fue la obtención de la concentración-alvo de 4 µg.kg-1 de propofol. Fueron cogidas tres muestras sanguíneas (a los 20, 40 y 60 minutos) para la dosificación del propofol por el método de la Cromatografia Líquida de Alta Performance.
RESULTADOS: Los Grupos S y M fueron considerados similares cuanto a la edad, altura, peso y sexo (p > 0,05). No hubo diferencia estadística significativa entre los dos grupos estudiados para los parámetros: PAS, PAD, FC, FiN2O, SpO2 de la hemoglobina y PETCO2 al final de la expiración. La comparación entre grupos en número de bolus repetidos de alfentanil no fue estadísticamente significativa. El índice bispectral (BIS), no presentó diferencia estadísticamente significativa entre M0 (vigilia) y los demás momentos en ambos grupos. Los valores Medianos de la Performance de Error (MPE) y los valores Medianos Absolutos de la Performance de Error (MAPE) mostraron diferencias estadísticas significativas entre los grupos en el momento 60. Valores medianos de la concentración sanguínea de propofol (µg.kg-1) mostraron diferencias estadísticas significativas entre M y S en el momento 60 y entre el momento 40 y 60 en el grupo S.
CONCLUSIONES: La anestesia con propofol usando los atributos farmacocinéticos de Marsh (Grupo M) presentó menor error en el cálculo de la concentración-alvo de propofol de 4 µg.kg-1. Además de eso, utiliza menor cantidad de propofol para obtener resultados clínicos semejantes. Por todas esas calidades debe ser el preferido para uso en niños ASA I y con edades entre 4 y 12 años.
Kruger-Thiemer 1 has equated a way of infusing a drug as a function of time, aiming at reaching and maintaining a constant concentration in the central compartment, provided its pharmacokinetics could be described by a linear multicompartmental model 2,3. This method, developed in clinical practice for continuous intravenous infusion, had a growing interest in the 70 s, though its commercial introduction came more recently, in the 90s 4.
Drug release is defined as automatic when a mechanical or electronic device adjusts the doses, requiring no human intervention (manual). Microcomputers, increasingly accepted in medicine, have allowed this automatic drug release. So, the pharmacokinetic model of a certain anesthetic drug, processed by a computer program, allows its administration according to the desired plasma concentration 5. Similarly, it is possible to determine when, after the anesthetic infusion withdrawing, the concentration compatible with consciousness recovery will be reached.
The success of this anesthetic technique is largely dependent on reducing operational costs. This type of infusion requires a microprocessor controlled pump like CACI - Computerized Assisted Continuous Infusion system 4,6-8, which is not available for most anesthetic procedures.
In 1993, Bailey 9 developed an alternative method for such infusion, which constantly varies between two or more fixed intravenous continuous infusion rates, which decrease in a controlled manner. Ultimately, he theoretically described a technique to calculate the rhythms of sequential infusions needed to get close to the constant blood level desired.
This method was adapted by Vianna 10-12 for propofol continuous infusion 11, using Marsh 13 and Short 14 pharmacokinetic parameters with the purpose of spreading the use of target-controlled concentration, that is, the maintenance of an approximately constant desirable blood concentration.
The aim of this study was compare, in clinical and laboratorial terms, Marshs 13 and Shorts 14 pharmacokinetic parameters used for target-controlled propofol infusion, associated to nitrous oxide, in children aged 4 to 12 years.
After the Faculdade de Medicina de Botucatu Ethical Committees, approval 41 pediatric patients of both genders, aged 4 to 12 years, physical status ASA I, scheduled for adenotonsillectomies, strabismus corrections and bone fractures open reductions under general anesthesia were included in the study. Patients were admitted to Hospital das Clinicas, Faculdade de Medicina de Bauru the day before surgery.
After admission, patients were clinically evaluated and parents or guardians were asked to authorize their inclusion on the study, as well as the use of clinical parameters of the anesthetic protocol.
Patients were randomly allocated into two groups, according to the pharmacokinetic program to be used:
GROUP S - SHORT (Shorts 14 pharmacokinetic parameters) - 3 mg.kg-1 bolus propofol and 254 µg.kg-1.min-1 propofol infusion for 30 minutes, followed by 216 µg.kg-1.min-1 propofol infusion for 30 minutes - 20 patients.
GROUP M - MARSH (Marshs 13 pharmacokinetic parameters) - 3 mg.kg-1 bolus propofol and 208 µg.kg-1.min-1 for 30 minutes, followed by 170 µg.kg-1.min-1 for 30 minutes - 21 patients (Table I).
The goal of propofol infusions in both groups was to obtain target 4 µg.ml-1 blood concentration.
After monitoring and venous accessing, anesthesia was induced with 30 µg.kg-1 alfentanil followed by 3 mg.kg-1 bolus propofol and 0.08 mg.kg-1 pancuronium for muscle relaxation. Next, patients were intubated and controlled mechanical ventilation was started with 60% N2O/O2, as well as propofol continuous infusion. Propofol bolus and maintenance infusion were administered through an infusion pump. Should the patient exhibit clinical changes indicating superficial anesthesia, 10 µg.kg-1 bolus alfentanil were given. No additional neuromuscular blocker doses were given. The last moment studied was at 60 minutes, even when surgery lasted longer.
Computer programs to calculate continuous infusion rates were: Short (PROCHIV) program and March (PROCRIV) program.
Intravenous propofol infusion was made through an infusion pump according to the formula developed by Vianna and Vane 15, equaling mass to drug volume, which is:
C = drug concentration I (µg.ml-1)
W = patients body weight (kg)
D = infusion rate ( µg.kg-1.min-1)
* constant (60 minutes = 1 hour)
This pump makes easy propofol infusion, since as you enter drugs concentration, patients weight and dose to be infused, the equipment automatically calculates the infusion rate in ml.h-1.
Monitoring consisted of ECG, pulse oximetry (SpO2), capnography (PETCO2) and blood pressure measured by auscultatory method. Hypnosis depth was assessed by a microprocessed EEG equipment (BIS).
Ventilation was mechanically controlled, with nitrous oxide inhalation (60%) in oxygen. Nitrous oxide inspired fraction (FiN2O) was evaluated a gas analyzer.
Four programs were developed to obtain approximately constant propofol blood concentration: Short (PROCHIV) program, Marsh (PROCRIV) program, Short (PROPOCHI) program and Marsh (PROPOCRI) program.
The first two programs Short (PROCHIV) and Marsh (PROCRIV) calculated propofol infusion rates needed to maintain almost constant blood concentration after a given bolus.
Starting by an execution command, the programs prompt for patients name, record number, age, weight, gender, anesthesiologists name, etc. Following, the initial propofol bolus was informed and the programs return the infusion rates to be used in a single screen.
The third (Short - PROPOCHI) and fourth (Marsh - PROPOCRI) programs calculate blood concentrations after any drug administration scheme. In fact, these programs either emulate or calculate propofol predicted concentration (Pc). Again, patients information is automatically asked. After confirmation, a screen is displayed with basic data about recommended dose ranges. Then, applied bolus and infusion rate are asked. The program accepts any dosage, even outside typical concentration ranges. A small window shows calculated concentration at every 25 s. New bolus or changes in infusion rate can be made at any time. The programs are always prompting for new information. If there is no new bolus or new infusion, one just inform value zero when asked. This is the case when the drug is no longer being administered, but emulation should continue to evaluate recovery conditions, which was not the objective of our study. Finally, results are stored in data files for curves visualization through any graphic processor. A list of results is also supplied.
Basically, programs solve the differential equations system by the finite differences method, also known as Eulers method. Programming language is BASIC.
Blood Propofol Measurement
At 20, 40 and 60 minutes (moment 20, moment 40 and moment 60) after beginning of anesthesia, 2 ml of venous blood samples were collected. These samples were maintained at 4 ºC in tubes with potassium oxalate and were used to determine blood propofol concentration (Cm). Blood propofol was measured by High Performance Liquid Chromoatography (HPLC) using a Shimadzu Mod. LC 10 device with fluorometric detector (Shimadzu F 535), with wavelength between 276 mm and 310 mm, pressure of 120 psi ± 20 and flow of 1.25 ml.min-1, according to Plummers 17 technique.
Measured propofol blood concentration (Cm) and propofol predicted concentration (Cp) by Short program (PROPOCHI) and Marsh program (PROPOCRI) were then statistically analyzed. Error Performance Median (EPM) was derived, in ± %, through following the formula:
EPM ± % = Cm - Cp / Cp x 100
Error Performance Absolute Median (EPAM) was also calculated, which result is similar to EPM, however without positive or negative value:
EPAM % = Cm - Cp / Cp x 100
Clinical parameters like bispectral index (BIS), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and hemoglobin oxygen saturation (SpO2) were registered every 5 minutes. For statistical analysis, those attributes were evaluated in the following moments:
Moment 0 - immediately before anesthetic induction
- control (M0);
Moment 5 - 5 minutes after beginning of propofol infusion - (M5);
Moment 10 - 10 minutes after beginning of propofol infusion - (M10);
Moment 20 - 20 minutes after beginning of propofol infusion - (M20);
Moment 40 - 40 minutes after beginning of propofol infusion - (M40);
Moment 60 - 60 minutes after beginning of propofol infusion - (M60);
FiN2O and PETCO2 were not evaluated in M0.
Friedmans tests were used to compare BIS, FiN2O, SatO2, Error Performance Median (EPM), Error Performance Absolute Median (EPAM) and propofol blood concentration between moments within each group. Mann-Whitney test was used to compare groups in each moment. Profile Analysis 18 was used for SBP, DBP, HR and PETCO2, because they present normal distribution.
Students t test was applied to check groups homogeneity regarding to age, height and weight. Fishers Exact test was used for gender 19.
Students t test was used to compare alfentanil bolus repetition between groups S and M.
There were no significant differences between moments and between groups in hemoglobin oxygen saturation (SpO2), nitrous oxide inspired concentration (FiN2O), end tidal CO2 partial pressure (PETCO2), systolic and diastolic blood pressure, heart rate and repeated alfentanil doses (p > 0.05).
There is currently an increasing interest of anesthesiologists in using intravenous hypnotics, analgesics and neuromuscular blockers intravenous continuous infusions. The therapeutic effect of different drugs is a function of their concentration in the biophase, which is determined by blood concentration. Blood concentration may be maintained by computer assisted infusion pumps. There is a commercially available equipment in Brazil for propofol infusion, called Diprifusor®. This microprocessed infusion pump uses pharmacokinetic parameters of adult patients, therefore it and is exclusive for them since childrens pharmacokinetics is very different from adults, especially when propofol is used 20. Propofol concentration curves in children are better described by a tricomparmental model, with a short initial half-life (1.5 to 4.2 minutes), due to redistribution process, followed by a second phase (9.3 to 56 minutes) associated to high metabolic clearance in the liver and in other large distribution volume sites. The third and final phase (209 to 475 minutes) reflects the slow elimination process of less vascularized tissues 21,22. So, in children, central compartment distribution volume (343 ml.kg-1) is higher as compared to adults (228 ml.kg-1). This determines the need to increase propofol doses during anesthetic induction. In adult patients, to reach a blood target-concentration of 4 to 5 µg.ml-1, 1.5 to 2 mg.kg-1 venous propofol are needed, while in children require higher doses 14, like 3 to 3.5 mg.kg-1. Propofol clearance is also increased in pediatric patients. Marsh 13 has shown in children propofol clearances of 32 to 57 ml.kg-1.min-1. In adult patients, this parameter was, in average, 27 ml.kg-1.min-1. So, higher propofol doses are required to achieve and maintain blood levels compatible with the hypnosis needed in anesthesia.
The aim of calculating predicted drugs blood concentrations by pharmacokinetic models is to obtain a rational regimen for those drugs administration.
The two major pharmacokinetic model techniques are: compartment model and exponential equations. According to Glass 4, the latter is a rough simplification for most drugs, while the former is more widely used for offering an intuitive understanding of the pharmacokinetic phenomenum, among other reasons.
For most drugs, this phenomenum can be mathematically reproducted by the three compartments model. The first, or central compartment, is defined as the compartment where the drugs can be sampled, that is, the blood. Drugs leave the central compartment by elimination, especially by kidneys and by distribution to other tissues as well 23.
However, Bailey 9 has shown that it is possible to obtain approximately constant drug blood concentrations using conventional infusion techniques.
This allows anesthesiologists working in places where computer assisted infusion systems are not available, like the majority in Brazil, to perform procedures very close to those automatically performed.
According to a suggestion of Kruger-Thiemer 1 and Glass 4, this anesthetic infusion regimen is called BET: a bolus (B) fills the whole central compartment reaching the desired drug concentration, followed by a constant infusion to replace the drug being eliminated (E) from this compartment by excretion or metabolism. Superimposed to it, another infusion, which exponentially decreases with time, is used to replace the drug being transferred (T) to peripheral compartments.
Through the three compartments model equations, it is very easy to assume that, in the steady state, a variable continuous infusion rate leads to a constant blood concentration given by:
I = Cpo - V1 . K10
I = constant infusion regimen [µg.kg-1.min-1]
Cpo = desired concentration [µg.ml-1]
K10 = elimination constant [min-1]
V1 = central compartment volume [l]
To prevent a concentration x time curve drop, Bailey 9 proposes an initial bolus followed by continuous infusion for 30 minutes. The infusion should be then adjusted at 1 hour intervals (30-90 min, 90-150 min, 150-210 min etc).
In fact, the numeric calculation program is executed based on the three compartments model which calculates infusion rates needed for the concentrations to reach a predetermined value in 30 min, 90 minutes and subsequent hours (Table II and Table III). In general, infusion rate is decreased in every stage but, depending on the initial bolus dose, it is possible that infusion may have to be increased from the first to the second stage.
Actually, the time in which the infusion rates are fixed could be any, and if stage intervals were decreased, concentration would deviate less from the target. Computer emulations generate results as precise as those obtained by Marsh 13 and Short 14.
The results obtained should be seen with some criticism, given the limitations of the three compartments model itself. Drug predicted blood concentration obtained by calculation is not exactly in agreement with patients actual blood concentration. This is due firstly to pharmacokinetic parameters obtained from measurements in a very small population. Statistically, one cannot assure that those samples are fully representative of the universe of individuals. Even if parameters are normalized by weight, gender and age, clinical status and physiological differences may vary 24. Moreover, even if drug blood concentration is exactly the same as the calculated one, concentration needed for a given response to a stimulation differs from patient to patient. On the other hand, the technique is justified because potential blood concentration deviations wouldnt go beyond drugs therapeutic window limits. That what was observed in this study: hemodynamic parameters and hypnotic levels were similar in both groups. This study also showed that individual variations occurred, part of the reason why collected data were different from those computer accurately calculated.
Another interesting result was similar BIS-evaluated hypnosis levels observed in both groups, showing that different propofol infusions determined by pharmacokinetic programs produce concentrations within the same therapeutic window. It must be remembered, however, that median BIS values were lower in Group S, with the exception of M5, which was influenced by the initial propofol bolus. These results are original, and there is no pediatric paper in the literature studying BIS related to propofol blood concentration (Table VI and Figure 1). There is one study evaluating hypnosis levels in children under sevoflurane 25,26 or sevoflurane associated to N2O 27.
There is no method able to compare analgesic depth between groups. The only data showing that groups were similar in this aspect was the inexistence of significant difference in alfentanil bolus administration. This complementation was minimal and restricted to 4 Group S and 5 Group M patients. This demonstrates the analgesic efficacy of 60% N2O associated to propofol.
This study has used, in an original manner, pharmacokinetic parameters obtained from two researches with children aged 4 to 12 years 13,14. For such, a software (PROCRIV, PROCHIV) was employed, based on a Baileys study 9 proposing a simplified method to maintain a drug blood concentration approximately constant. The technique was developed to enable anesthesiologists to maintain a desired target blood concentration approximately constant. After an arbitrary bolus dose, decreasing infusion rates are calculated to maintain a stable blood level. These infusion rates are obtained from equations which calculate sequential infusion rate schedules. The accuracy of this technique was measured by Error Performance Median (EPM). It is an international consensus to consider acceptable for clinical use programs using pharmacokinetic parameters where EPM is equal to or lower than 30. EPM results in our study showed that median levels of 8.4 in moment 20 for the Marsh group. After this, EPM increased to 16 in moment 40 and decreased to 4.6 in moment 60, showing that, after 1 hour, predicted concentration had come close to measured concentration. Short program 14 had an opposite behavior: EPM was 16 at 20 minutes, followed by 12.1 and 52 at 40 and 60 minutes of propofol infusion (Table VII and Figure 4). Our results have shown that Marshs 13 pharmacokinetic parameters had a good performance and remained within limits of ± 30. When predicted and measured concentrations were compared through Error Performance Absolute Median (EPAM), absolute values of 28.7 in moment 20, 33.2 in moment 40 and 23.6 in moment 60 were obtained for Group M; for Group S those values were 44.7 in moment 20, 36.3 in moment 40 and 53.8 in moment 60. These results have shown that during 1 hour of propofol infusion there was an uniformity of results with Marshs pharmacokinetic parameters 13, while in Group S there was a cumulative effect, reflecting in a statistically significant difference between groups in moment 60.
Our major objective was to evaluate whether a pharmacokinetic parameter for propofol infusion associated to N2O in children could significantly influence hypnosis and anesthesia (Table VI and Figure 1). There were no significant differences in hemodynamic parameters (systolic and diastolic blood pressure and hear rate) for both groups. SpO2, nitrous oxide inspired concentration (FiN2O) and PETCO2 showed also no significant difference among moments and between groups. Also, the amount of additional analgesics was similar between groups, showing that pharmacokinetic programs are clinically equivalent. This result is understandable because, even with pharmacokinetic differences, target blood concentrations associated to N2O remained within the therapeutic window. In our study, pharmacokinetic parameters were obtained from pediatric patients from two continents (Europe and Asia) and applied to Brazilian children. It is more likely that Shorts pharmacokinetic program, based on Hong-Kong children, has overestimated Brazilian pediatric patients´ target blood concentration. Conversely, Marshs pharmacokinetic parameters obtained from European children, came closer to 4 µg.ml-1 propofol target concentration in our patients.
Clinically, patients had similar behaviors, when accessed three a more precise technique to evaluate hypnosis, like the microprocessed EEG equipment - BIS (Table VI and Figure 1). From the laboratorial point of view, by measuring propofol blood concentration, this similarity was not seen (Table VII, Table VIII and Table IX, Figure 2, Figure 3 and Figure 4).
Concluding, the comparison between Marshs 13 and Shorts 14 parameters has shown that both computer programs can be used in pediatrics patients, but our preference is for PROCHIV-Marsh program for using less propofol associated to N2O, for reaching a more accurate target concentration and inducing adequate hypnosis levels in children aged 4 to 12 years.
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Dr. Pedro Thadeu Galvão Vianna
Address: Deptº de Anestesiologia da FMB UNESP
Distrito de Rubião Junior
ZIP: 18618-970 City: Botucatu, Brazil
Submitted for publication August 15, 2001
Accepted for publication November 6, 2001
* Received from CET/SBA do Departamento de Anestesiologia da Faculdade de Medicina de Botucatu (FMB UNESP). Trabalho financiado pela FAPESP