K Lim, T Lim, W Wong
anaesthetics, effect compartment, intravenous, pharmacokinetics, thiopental
K Lim, T Lim, W Wong. Pharmacokinetics Of Thiopental In Patients With Cardiovascular Disease. The Internet Journal of Anesthesiology. 2006 Volume 14 Number 1.
e) of thiopental in patients with cardiovascular (CVS) disease.
e in patients with CVS disease will be under-estimated if a pharmacokinetic model derived from generally well patients is used. A new model derived to describe patients with CVS disease revealed that both the processes of drug distribution and elimination are slower in this group of patients. However, the effect compartment equilibrium half-time was also lower.
e at loss of the eyelash reflex for patients with or without CVS disease is 8.51 µg ml-1.
Anaesthetists deal with a large variety of patients, some of whom may have major physiological derangements. However, most dosing regimens have been developed based on the pharmacokinetics of the drug in healthy volunteers or in patients who are generally well. When giving thiopental to ill patients, it is considered advisable to inject the drug slowly to avoid an over-shoot of the plasma concentration, which in turn may lead to the undesirable depression of other systems.
After a bolus dose, there is a lag between the time a particular plasma concentration is reached, and the manifestation of the corresponding effect at the same concentration at steady state. Slow injection decreases this time lag, leading to a lower induction dose1. In patients without systemic diseases, the hysteresis-free effect compartment concentration at induction of anaesthesia is unaffected by the method of injection2.
The use of pharmacokinetic parameter values derived from generally well patients in patients with cardiovascular (CVS) disease has not been fully investigated. Body weight, age and cardiac output have been previously reported as possible predictors of thiopental dose requirements3,4. The presence of CVS disease is likely to have an effect on the cardiac output, which could affect thiopental pharmacokinetics.
The aim of this study is to determine whether the predicted effect compartment concentration (
Materials and Methods
The study was approved by the local clinical research ethics committee. Eighty patients, American Society of Anesthesiologists (ASA) physical class 1 or 2 scheduled for elective surgical operations, gave informed consent for the study. Forty patients had evidence of CVS disease. This included patients with a history of hypertension or ischaemic heart disease, symptoms or physical signs suggestive of CVS disease, or evidence on ECG examination. Another 40 patients without evidence of CVS disease formed the control group. Patients with clinical or laboratory evidence of cardiac failure were excluded from the study.
Patients were randomized to receive thiopental either as a single bolus or as a series of small boluses for induction of anaesthesia. This resulted in a total of 4 groups:
Group 1: Patients with CVS disease who were given a single bolus
Group 2: Patients with CVS disease who were given multiple boluses
Group 3: Patients without CVS disease who were given a single bolus
Group 4: Patients without CVS disease who were given multiple boluses
All patients also received oral midazolam 3.75 mg 1 to 2 hours before induction of anaesthesia. On arrival in the operation theatre, an intravenous cannula was inserted into a forearm vein for infusion of drugs and fluid. A bolus dose of fentanyl 100 g was given 1 minute pre-induction.
Patients in groups 1 and 3 received a single 3 to 3.5 mg kg-1 bolus dose injected over 10 seconds. Patients in groups 2 and 4 were given 50 mg bolus doses of thiopental every 15 seconds until loss of the eyelash reflex was demonstrated. The eyelash reflex was tested every 2.5 seconds, and the time at which the reflex was lost was recorded. After induction of anaesthesia was successfully achieved, patients were maintained using a standard anaesthetic technique.
The central compartment concentration was initially predicted using the model reported by Stanski and Maitre5. Effect compartment concentration (
In order to adapt the parameter set for patients with CVS disease, we used the Microsoft Excel Solver to minimize the difference between the mean
We then repeated the process in a two stages instead of pooling all the data together. To do this, each group was subdivided equally into 4 sub-groups and labelled 1a, 1b, 1c, 1d … up to 4d. Four corresponding sub-groups were then combined, e.g. sub-groups 1a, 2a 3a and 4a were combined into Combination A. In this fashion, 4 combinations: A, B, C and D were obtained. Pharmacokinetic modelling was then carried out using the technique described above on each of the combinations. The derived parameter values from each combination were then prospectively tested on patients from the other sub-groups.
Differences between groups were tested using ANOVA, Student's
Demographic data is shown in Table 1.
Mean age was significantly different between groups (
Using Stanski's model, the mean
The model derived using the two-stage technique was very similar to the one derived using the pooled technique. Prospective testing of the parameter sets derived by the 4 sub-group combinations revealed that there was no significant difference between the predicted
In this study, we found that when the same pharmacokinetic parameter set is used to predict
In addition, we assumed the
The value for the fast inter-compartment rate constant (
One unexpected finding was the decrease in the effect compartment equilibrium half-time. This means that when the plasma concentration is kept constant, the effect compartment would equilibrate faster with the plasma. Again, this could be an effect of a decreased cardiac output. Transit time through the brain could be slower in patients with CVS disease, allowing more time for equilibration to occur. This has the effect of allowing the brain (where the effect takes place) to have a concentration closer to that of the arterial concentration. Mathematically, this would translate to faster equilibration reflected as a lower half-time.
Figure 1 shows the effect compartment concentration – time profile after a single 3 mg kg-1 bolus dose of thiopental in patients with and without CVS disease. The faster rise in patients with CVS disease is a consequence of the slower distribution to the periphery. The more prolonged effect is because of slower elimination and redistribution. What is more worrying is that
The anaesthetic technique in this study included the use of midazolam as premedication, and intravenous fentanyl pre-induction. The use of midazolam premedication has been reported to decrease the induction dose of thiopental, thus decreasing the effect compartment concentration required for induction anaesthesia7. In addition, older patients are more sensitive to midazolam and fentanyl8,9. While all this would have added variability to the results, it was not appropriate to subject patients with CVS disease to pre-operative anxiety, as well as not obtunding the haemodynamic effects of endotracheal intubation.
It would have been appropriate to attempt deriving the predicted effect compartment concentration when using a continuous infusion as well. However, during the infusion, patients may experience a phase of restlessness before loss of consciousness occurs. We felt that this might cause an increase in heart rate and / or blood pressure, which would not be desirable in patients with cardiovascular disease.
In conclusion, pharmacokinetic parameter derived from generally well patients will under-predict the effect compartment concentration in patients with mild cardiovascular disease. This is likely because of a change in pharmacokinetics in these patients. Both the processes of distribution and elimination are slower, leading a faster onset and delayed recovery. We found the effect compartment concentration at loss of the eyelash reflex for patients with cardiovascular disease to be 8.51 g ml-1.
Dr. T.A. Lim Anaesthesiology Unit Faculty of Medicine and Health Sciences Universiti Putra Malaysia 43400 UPM Serdang Selangor Darul Ehsan Malaysia Tel: (603) 8947 2487 Fax: (603) 2050 1001 E-mail: firstname.lastname@example.org