Introduction

Planned simultaneous administration of multiple drugs exploits the beneficial effects of drug interactions. A synergistic interaction should bring about a decrease in adverse effects while maintaining the desired pharmacological effects.

Modern day anaesthetic practice attempts to apply this principle to the induction and maintenance of anaesthesia. However, the two commonly used intravenous anaesthetic agents, propofol and thiopental, act via the same mechanism and are expected to interact additively.

Vinik and colleagues reported that propofol and thiopental given as separate bolus injections resulted in an additive interaction ₁ . Jones and colleagues found the same when giving an admixture of the two drugs after a dose of fentanyl ₂ . Both the above studies used an isobolographic approach, and the doses of propofol and thiopental were given in predetermined ratios.

In this study, propofol and thiopental were given simultaneously during co-induction of anaesthesia in patients without preoperative sedatives or narcotics. The aim of the study is to confirm the additive interaction between propofol and thiopental under different dosing regimens. Similar to previous studies, the first part of this study involved giving propofol and thiopental in fixed ratios. In the second part, the dose ratio of the two drugs was allowed to vary.

Materials and Methods

The study was approved by the local clinical research ethics committee. Ninety patients, American Society of Anesthesiologists physical class 1 or 2, scheduled for elective surgical operations gave informed consent for the study. Patients with a body weight above 85 kg, and patients with evidence of cardiovascular disease or a history of sensitivity to propofol or thiopental, were excluded. Patients were not given any premedication or opioids pre-operative.

In the first part of the study, 50 patients were randomized to one of five groups and were given a specific drug or drug combination for induction of anaesthesia. Drug mixtures were prepared within 30 minutes of the time of induction.

Group 1a: Propofol 10 mg ml ^-1 Group 1b: Propofol 7.5 mg ml ^-1 plus thiopental 6.25 mg ml ^-1 Group 1c: Propofol 5 mg ml ^-1 plus thiopental 12.5 mg ml ^-1 Group 1d: Propofol 2.5 mg ml ^-1 plus thiopental 18.75 mg ml ^-1 Group 1e: Thiopental 25 mg ml ^-1

In the second part of the study, patients were randomized to one of two groups. Within each group, patients were randomized to receive one of three bolus doses of a study drug. Each patient was given this bolus dose over 1 to 2 seconds, followed immediately by an infusion of the second drug.

Group 2a: Bolus dose of thiopental (50, 75 or 100 mg), followed by an infusion of propofol (10 mg ml ^-1 ). Group 2b: Bolus dose of propofol (20, 30 or 40 mg), followed by an infusion of thiopental (25 mg ml ^-1 ).

In all groups, the study drug or drug combination was infused at a rate of 150 ml min ^-1 , 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.

Data analysis

Results

A total of 27 male and 63 female patients were admitted into the study. The mean age, mean weight and gender distribution are given in Table 1. There were no significant differences in demographic data between groups. Table 2 shows the dose and predicted drug concentration at loss of the eyelash reflex.

Figure 1

Table 1: Patient data (mean (SD)). Prop:Thio ratio refers to the ratio of propofol (10 mg ml ) to thiopental (25 mg ml ) in terms of volume. B = bolus ; I = infusion.

Figure 2

Table 2: Dose and predicted drug concentration at loss of the eyelash reflex (mean (SD)).

Figure 1 shows the relationship between the mean doses of propofol and thiopental at loss of the eyelash reflex. There was no significant difference between the mean dose for each group and its corresponding predicted dose on the line of addition. Using linear regression, the average dose at loss of the eyelash reflex for propofol and thiopental were 1.14 mg kg ^-1 and 2.49 mg kg ^-1 respectively.

Figure 2 shows the distribution of the mean predicted central compartment concentrations. In Group 2b, the mean concentrations of propofol and thiopental were significantly higher than those expected if the line of addition was followed (p<0.001).

Figure 3 shows the distribution of mean effect compartment concentrations. All predicted concentrations were not significantly different from the line of addition.

Figure 3

Figure 1: Relationship between mean doses of propofol and thiopental at loss of the eyelash reflex. Each circle represent the mean dose derived from a group of patients.

The line joining the mean doses of propofol and thiopental when given alone, is the line of addition. Isobolographic analysis reveals an additive interaction.

Figure 4

Figure 2: Propofol vs. thiopental predicted central compartment concentration at loss of the eyelash reflex. Each circle represents a group of patients. Isobologrphic analysis suggest that in Group 2b (open circle), the relationship is antagonistic.

Figure 5

Figure 3: Propofol vs. thiopental effect compartment concentration at loss of the eyelash reflex. Each circle represents a group of patients. There is no significant difference between any circle and its corresponding point on the line of addition.

Discussion

In clinical practice, it is not unusual for several drugs to be given together in order to obtain a specific pharmacological effect. However, combining drugs with similar effects may result in synergistic, additive or antagonistic interactions. This was reported in a recent study on anticonvulsants ₆ .

The same has been shown with pharmacological agents used to produce hypnosis. Midazolam has been reported to act synergistically with propofol and thiopental ₇,₈ . In contrast, propofol and sevoflurane interact in a simple additive manner to produce loss of consciousness ₉ . The interaction between nitrous oxide and propofol for the suppression of blood pressure elevation also appears to be additive ₁₀ .

This study confirmed earlier reports that the hypnotic effect of propofol and thiopental when given together is additive ₁,₂,₁₀ . However, the design of our study is quite different from the earlier studies.

In the study by Vinik and colleagues, the doses of propofol and thiopental which were given to the patients were fixed, and the end-point was reached in some patients but not in others ₁ . In our study, the doses of propofol and thiopental were allowed to vary according to the patients' requirement. All of our patients reached the pharmacodynamic end-point. Despite the differences in methodology, the average dose of propofol and thiopental obtained in Vinik's study were very close to the values we obtained.

Unlike the study by Jones and colleagues, we did not give opioids to any of our patients before induction of anaesthesia ₂ . Opioids have been reported to act synergistically with propofol and thiopental ₁₂,₁₃ . When all three drugs are given together, the extent to which fentanyl affects the propofol dose may not be the same as the extent to which it affects the thiopental dose. The quantity of effect from three-drug combinations is difficult to predict. Short and colleagues reported that the effect of a midazolam-propofol-alfentanil combination was less than expected although it was still synergistic ₁₄ . Our study was designed to avoid such a situation.

Most isobolographic studies use fixed drug dose ratio combinations. Whether the method can be adapted to variable drug dose ratios has not been well documented. This study illustrates that it is possible to use isobolographic analysis when drugs are given in variable dose ratios. Such a condition better resembles the actual clinical situation.

We also demonstrated that the isobolographic analysis could be applied to effect compartment concentrations. However, the same could not be applied to predicted central compartment concentrations. In the group of patients who received a bolus of propofol followed by an infusion of thiopental, the relationship appeared to be antagonistic. This is most likely because of a delay in the equilibration between the central and effect compartments. This results in the predicted central compartment concentration being higher than expected, giving an impression that the relationship is antagonistic. Our study therefore supports the practice of using effect compartment concentrations, rather than central compartment concentrations, to predict effect.

The practical uses of propofol-thiopental combinations have been previously studied. Pre-treatment or co-administration of thiopental has been reported to reduce the incidence of pain on injection with propofol ₁₀,₁₅,₁₆,₁₇,₁₈ . The propofol-thiopental admixture has also been shown to produce suitable conditions for laryngeal mask insertion ₁₉ . Furthermore, giving such an admixture for induction of anaesthesia produced less hypotension compared to giving propofol alone ₂,₁₀,₁₉ .

One of the worries with mixing two drugs is that the undesirable effects of both drugs would contribute to the overall patient morbidity. It has been argued that adding thiopental to propofol for induction would remove some of the advantages associated with propofol ₂₀ . However, studies have shown that the mean discharge time in patients who were given a propofol-thiopental admixture was not different from patients who were given propofol alone or with lignocaine ₂₁,₂₂ . These studies also reported that the incidence of severe nausea or need for anti-emetics were not increased.

In conclusion, we studied the hypnotic effect of propofol and thiopental when given together and found the effect to be additive at the range of doses used for induction of anaesthesia.

Correspondence to

Dr. W.H. Wong 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: talim@medic.upm.edu.my