M. A. Khan  ( Department of Anaesthesiology, The Aga Khan University Hospital, Karachi. )
F. A. Khan  ( Department of Anaesthesiology, The Aga Khan University Hospital, Karachi. )

Co-induction is defined as the concurrent administration of two or more drugs that facilitate induction of anaesthesia.1 It was criticized for a long time because of fear that combination therapy may also combine the side effects, thus increasing the risk to the patients.2 Better understanding of the pharmacokinetics and pharmacodynamics as well as addition of many new drugs to the formulary has made it possible to accept the rational use of combination therapy.3,4
During the last decade co-induction of anaesthesia has been extensively studied with propofol in a number of combinations.1-6 The most common disadvantages with propofol are its greater cost (Pak Rs. 330/-) as compared to Thiopentone (Pak Rs.52), high incidence of pain on injection7 (50 - 100%) and relatively more hypotension as compared to thiopentone.8
Thiopentone is the most commonly used anaesthesia induction agent in Pakistan. Objective of our present study was to compare and evaluate co-induction of anaesthesia with a combination of thiopentone and midazolam and compare it to thiopentone induction alone. We also evaluated the quality of induction by observing an additional end point of hypnosis i.e., loss of response to a tetanic stimulus.

After approval from the Human Subjects Protection Committee of the university, informed consent was obtained from 90 ASA I and II patients who were then enrolled in the study in a blind, randomized and controlled manner. Blindness was ensured by preparation and administration of the drugs by an anaesthetist unconnected with the study. Subjects included both males and females between the age of 20 and 60 years, who were randomly, divided in three groups A, B and C. No premedication was given. Baseline systolic, diastolic, mean arterial pressure, heart rate and oxygen saturation with pulse oximetre was recorded using Datex cardiocap II monitor.
The study drugs were labeled as Drug 1and Drug 2. Drug 1was 3 mls of normal saline (placebo) in control group (A), while it was midazolam 0.02 mg.kg-1 in group B and group C. Drug 2 was thiopentone 2.5% in a 25mls syringe. Thiopentone (Drug 2) was given in a dose of 4 mg.kg-1 in group A patients, 3 mg.kg-1 in group B patients and 2 mg.kg-1 in group C patients, one minute after administration of Drug 1.
Haemodynamic parameters were recorded as baseline values, immediately following administration of Drug 1 and Drug 2 and every minute for five minutes. Patients were instructed to start counting loudly at the time of induction. Time of start of induction was noted. End point of hypnosis was assessed by noting the time of loss of verbal contact and loss of eyelash reflex. After the loss of eyelash reflex, a transcutaneous 50Hz tetanic stimulus was given for five seconds over the ulnar nerve at the wrist. The tetanic stimulus was taken as an equivalent of a painful stimulus9,10 and patients were judged to be anaesthetized if they did not move in response of the tetanic stimulation.
Supplemental top up boluses of thiopentone (25 mg) were given to patients in whom anaesthesia was found to be inadequate, as judged by head or limb movements in response to tetanic stimulation. Total number of supplemental boluses of thiopentone were noted on the chart.
Any untoward effects like desaturation, bradycardia, tachycardia, hypotension, hypertension, dysrythmias, pain on injection, hiccups and hypersensitivity reactions were also noted. Desaturation was defined as mild when oxygen saturation fell below 95% but remained above 90%, moderate between 86 % and 89 % and severe if it fell below 86%. Bradycardia was defined as the heart rate below 60 beats.min-1, and tachycardia as heart rate above 100 beats min-1. Hypertension was defined as blood pressure values (systolic, diastolic and mean), 20% above baseline and hypotension as 20% below the baseline values.

Statistical Analysis

Power analysis was used to determine the number of patients based on the assumption that for an a-value of 0.05 and a power (1-ß) of 0.8, 30 patients were required in each group. Variables were entered and analyzed on statistical package epi-info 6. The mean change in systolic, diastolic, mean arterial pressure, heart rate, and time to achieve anaesthesia were compared between the three groups using ANOVA. Categorical variables were compared using chi-square test; p-value of less than 0.05 was considered significant.

Results

Demographic data

Table 1 shows the demographic data. No significant difference was observed in age, weight and height between groups.

Hypnosis

The end point of hypnosis was assessed by loss of verbal contact, loss of eyelash reflex and loss of response to tetanic stimulation (50 Hz), as shown in table 2.
Loss of verbal contact, occurred earlier in group B (28.6 ± 6) seconds. The values for group A were 29.1 ± 5 seconds and for group C were 30.2 ± 6 seconds.
Loss of eyelash reflex was earliest in group B, 36.2 ± 8 seconds. The values were 39.4 ± 7 and 40.3 ± 8 seconds in group A and group C respectively.
Loss of response to tetanic stimulation. Patients in group B achieved anaesthesia in shortest time when this criteria was used as the end point of anaesthesia (40.6 ±8 seconds). This was significantly less (p < 0.05) when compared with group A (45.8 ± 7 seconds) and group C (50.4 ± 2 seconds). Although the time taken by patients in group A was less than those in group C but the difference was not statistically significant.

Supplemental boluses requirement during induction

Top up supplemental boluses of thiopentone were given to patients who showed signs of inadequate anaesthesia e.g. head or limb movement on application of tetanic stimulation (50Hz). The group breakdown of number of supplemental bolus requirement is shown in table 3. Patients in group C needed significantly more top up boluses per patient as compared to the other groups. The difference was statistically significant when group A and B were compared with group C (p<0.05) for the total supplemental boluses given.

Cardiovascular data

Systolic blood pressure: the changes in systolic blood pressure compared to the baseline are shown in figure 1. The mean change in the systolic blood pressure was in positive direction. No significant difference in the magnitude of change was observed among the groups except between groups A and C, one minute after administration of drug 2 (p < 0.05). Systolic pressure in group B showed least variation from the baseline.
Diastolic blood pressure: These changes are shown in figure 2. Statistically significant difference in the magnitude of change was seen between groups A and B, and group A and C one minute after administration of drug 1. There was also significant difference (p<0.05) between groups A and C at one minute, and between group B and C at five minutes after administration of drug 2. Group B again showed the least variability.
Mean arterial pressure: The changes are shown in figure 3. Statistically significant difference was observed between group B and C at 5 minutes after giving drug 2 (p<0.05). The overall data showed a more stable mean arterial pressure in group B patients.
Heart rate: The changes are shown in figure 4. Data showed no statistically significant difference between the groups but heart rate was clinically more stable in group B patients.

Complications

Desaturation: Seventeen patients in group A, 18 in group B and 21 patients in group C showed a decline in oxygen saturation from the baseline values. This data is presented in table 4. The values were not statistically different between the three groups.
Bradycardia: Non of the patients in group B developed bradycardia as compared to four patients in group A and one in group B. The difference among the groups was not statistically significant.
Tachycardia: Five patients in group A, eight in group B and eight in group C developed tachycardia. This difference was not statistically significant.
Hypotension: Four patients in group A, three in group B and three in group C developed hypotension.
Hypertension: Two patients in group A, four in group B and seven in group C developed hypertension. The difference was not statistically significant.
Pain on injection: Three patients in group A, one in group B and non in group C complained of pain on injection.
Arrythmias: No patient developed arrhythmia in either group.
Hiccups: Only one patient in group B developed hiccups.
Hypersensitivity reactions: No patient in any group developed a hypersensitivity reaction.

In conclusion, co-induction of anaesthesia with midazolam 0.02 mg.kg-1 and thiopentone midazolam 3 mg.kg-1 was associated with a smooth and significantly faster induction, better airway control, greater haemodynamic stability and lesser incidence of untoward effects compared to midazolam 0.02 mg.kg-1 and thiopentone 2 mg.kg-1 or thiopentone 4 mg.kg-1 alone.
When loss of verbal contact and loss of eyelash reflex were taken as the end point of induction, co-induction with midazolam 0.02 mg.kg-1 reduced the induction dose of thiopentone by 50% but this dose of thiopentone was inadequate to produce satisfactory level of anaesthesia when a tetanic stimulus (50 Hz) was taken as the end point. Thiopentone when reduced by 25% of its induction dose in combination with midazolam 0.02 mg.kg-1 produced the best and satisfactory results.

We are grateful to Mr. Azam Ali, Bio-statistics, Community Health Sciences, Mr. Ashar Minai, Statistician, ISD Department, Mr. Hamza, Incharge Learning Resource Center and Mrs. Fauzia Basaria, Instructor Community Health Sciences, The Aga Khan University Hospital, for their kind help in data analysis.

Objective: To evaluate improvement in quality of anaesthesia induction using thiopentone and midazolam for co-induction of anaesthesia. An additional end point was taken as loss of response to a tetanic stimulation (50 Hz) delivered for 5 seconds after the loss of verbal contact and eyelash reflex.

Methods: Ninety ASA I and II patients, within the age range of 20-60 years were studied. Patients were randomly divided into three equal groups; A, B and group C

Results: Onset of induction and loss of response to a tetanic stimulation was achieved earlier in group B as compared to the other study groups (p<0.05).

Conclusion: Co-induction with midazolam 0.02 mg.kg-1 followed by thiopentone 3 mg.kg-1 was superior to other two groups. Induction of anaesthesia in this group was found to be smoother and faster, provided better hemodynamic stability, better airway maintenance and with lesser incidence of untoward effects (JPMA 53:542;2003).