|Year : 2013 | Volume
| Issue : 2 | Page : 110-113
Co-induction effects of midazolam, thiopentone and ketamine with propofol in general anesthesia
Gojendra Rajkumar, Rupendra Thokchom, Pankaj Chandra Pradhan, Maniram KH Singh, Hemjit T Singh, Ratan N Singh
Department of Anesthesiology, Regional Institute of Medical Sciences, Imphal, Manipur, India
|Date of Web Publication||19-Nov-2013|
Department of Anesthesiology, Regional Institute of Medical Sciences, Imphal - 795 004, Manipur
Source of Support: None, Conflict of Interest: None
Objective: To evaluate whether the co-induction technique affects the total induction dose requirement of propofol and thereby reduce associated hemodynamic adverse effects. Materials and Methods: 120 american society of anesthesiologist (ASA) 1 and 2 patients undergoing general and gynecological surgeries under general anesthesia were randomly divided into four groups, i.e., group 1: Normal saline (control group), group 2: Midazolam, 0.03 mg/kg body weight, group 3: Thiopentone, 1 mg/kg body weight and group 4: Ketamine, 0.3 mg/kg body weight. After measuring the baseline hemodynamic variables and 2 min after study drug was given, propofol was administered 30 mg/10 s till the end points were reached -loss of verbal command or eyelash reflex. The total dose of propofol used and hemodynamic parameters were recorded following induction of anesthesia and the study was taken as completed and the rest of anesthesia proceeded as per standard technique. Results: Our study reveals that the total induction dose of propofol was reduced by 33.92% (group 2), 35.08% (group 3), and 42.69% (group 4) from that in the control group (group 1). The fall in mean arterial pressure from baseline in the midazolam (group 2), thiopentone (group 3) and ketamine group (group 4) was 10.88%, 14.58%, and 8.37% respectively. Conclusion: Ketamine reduced the induction dose requirement of propofol to the greatest degree and though, all three co-induction agents offered some degree of hemodynamic stability, ketamine provides the best cardiovascular stability.
Keywords: Co-induction, Hemodynamic responses, Ketamine, Midazolam, Propofol, Thiopentone
|How to cite this article:|
Rajkumar G, Thokchom R, Pradhan PC, Singh MK, Singh HT, Singh RN. Co-induction effects of midazolam, thiopentone and ketamine with propofol in general anesthesia. J Med Soc 2013;27:110-3
|How to cite this URL:|
Rajkumar G, Thokchom R, Pradhan PC, Singh MK, Singh HT, Singh RN. Co-induction effects of midazolam, thiopentone and ketamine with propofol in general anesthesia. J Med Soc [serial online] 2013 [cited 2023 Jan 29];27:110-3. Available from: https://www.jmedsoc.org/text.asp?2013/27/2/110/121578
| Introduction|| |
Propofol has been used in recent years as an effective alternative to the time-tested thiopentone for intravenous induction of anesthesia. Induction with propofol is smoother, almost equally rapid, has rapid awakening and orientation times, better intubating conditions and upper airway integrity compared to thiopentone sodium. 
However, the major disadvantages of rapid induction with propofol are impaired cardiovascular and respiratory function which may put patients at greater risk from hypotension, bradycardia, and apnea. A decrease of 26-28% of systolic blood pressure, 19% of diastolic blood pressure and 11% of mean arterial pressure (MAP) without changes in stroke volume and cardiac output are observed when anesthesia is induced with 2 mg/kg body weight of propofol. ,
The concept of co-induction of anesthesia has come forward by administering small doses of sedative or other anesthetic agents so as to decrease the dose requirement of the induction agent to make the quality of anesthesia better with improvement in hemodynamic stability, i.e., with fewer side-effects, and reduction of cost of expensive inducing agents such as propofol.
A number of co-induction techniques have been investigated such as opioids,  barbiturates like thiopentone sodium,  benzodiazepines like midazolam,  and ketamine. 
In view of the present popularity of propofol in the use of induction of anesthesia, we have taken up this study to evaluate whether the co-induction technique affects the total induction dose requirement of propofol and thereby reduce associated hemodynamic adverse effects.
| Materials and Methods|| |
After obtaining approval from the institutional ethical committee and written informed consent, 120 patients of ASA 1 or 2, aged 18-60 years, of either sex undergoing elective general and gynecological surgeries under general anesthesia were included in this randomized, doubled blind study. Patients with significant medical and psychiatric history, history of allergic to any of the study drugs and those taking benzodiazepines, opioids or analgesics were excluded.
Baseline measurement of blood pressure, pulse rate and arterial O 2 saturation were taken in the operation theatre. No premedication was given to any of the patients. After pre-oxygenation for 3 min, all patients received one of the co-induction agents intravenously (I.V.) which were randomly allocated according to computer generated random numbers as follows:
Group 1: Normal saline (control group)
Group 2: Midazolam, 0.03 mg/kg body weight
Group 3: Thiopentone, 1 mg/kg body weight
Group 4: Ketamine, 0.3 mg/kg body weight
Each group consisted of 30 patients. The co-induction agent was prepared in a 5 ml syringe by a separate anesthesiologist and the total volume of the study drug was made to 3 ml and it was disguised by a brown paper-wrap. Two minutes after the co-induction agent was injected, each patient received propofol 30 mg (I.V.) every 10 s until the loss of response to verbal command or loss of eyelash reflex, whichever earlier. All the patients were continuously engaged in conversation during the induction. When the patient stopped responding to verbal command or loss of eyelash reflex, propofol injection was stopped at this point and the facemask was firmly applied. In the case of any response to placement of facemask, additional dose of propofol was given. A separate observer assessed this; patient and the observer were blind to the drug combination being used. Heart rate (HR), arterial blood pressure and electrocardiogram changes were observed using automated multichannel monitor at the end of induction. The study was taken as complete at this point and further anesthetic technique was not influenced by this study. The anesthesia continued according to the standard practice. The total dose of propofol used for induction was recorded.
Statistical analysis was done on the various data obtained which includes demographic characteristics, the total induction dose of propofol, HR and arterial blood pressure using the independent and paired 't'-test, ANOVA and Chi-square test wherever appropriate. A 'P' value of less than 0.05 was considered statistically significant.
| Results|| |
The four groups were identical regarding age and body weight. The number of female patients outnumbered that of males in all the four groups though not statistically significant [Table 1]. The total induction dose of propofol [Table 2] was reduced significantly by 33.92% in group II, 35.08% in group III and 42.69% in group IV from that in group 1 (control) (P < 0.001). The least mean total induction dose of propofol was required for group 4 (propofol-ketamine) (P < 0.001) and highest for group 1 (control). The mean dose required to induce anesthesia was also lower in group 2 (propofol-midazolam) and group 3 (propofol-thiopentone) compared to group 1 (P < 0.05). There was a rise in mean HR following induction in all the groups [Table 3]. Group 1 patients had a significant increase in HR when compared with the other three groups (P < 0.05). Further analysis shows that patients in group 2 had a significant increase in HR than group 3 and group 4 (P < 0.05).
It was observed that at the end of induction, there was a significant fall in systolic blood pressure from the baseline [Table 4] in all the four groups (P < 0.05). However, group 4 patients had the minimum variation in systolic blood pressure compared to other three groups (P < 0.05). Similar fall in the diastolic blood pressure following induction [Table 5] was seen in all the groups (P < 0.05) with group 4 having the least variation compared to the rest (P < 0.05). The fall in the MAP from baseline in the midazolam (group 2), thiopentone (group 3) and ketamine group (group 4) was 10.88%, 14.58% and 8.37% respectively [Table 6]. MAP also follows the same pattern, i.e., statistically significant reduction following induction in all the groups (P < 0.05) with the least fall in the MAP in group 4 when compared to the other three groups (P < 0.05).
| Discussion|| |
All the three co-induction agents were effective in reducing the induction dose of propofol considerably compared to control (saline). Reduction in the induction dose of propofol following midazolam is probably due to the synergistic interaction between the two drugs.  So too, may be the case with thiopentone,  as midazolam, thiopentone and propofol act on a common receptor site, the gamma amino butyric acid (GABA) receptors. Synergism has been reported between agents with known functional link in the central nervous system. , Ketamine, on the other hand, acts by antagonism of NMDA receptors while propofol acts on GABA receptors. Therefore, the reduction in the dose of propofol required for induction when used with ketamine cannot be explained by a mechanism of synergism as these two agents act via distinctly different receptors. Hui et al.  suggested a simple additive interaction of sedative effects of the two drugs for this.
When used in the recommended dose of 2-2.5 mg/kg propofol almost always causes fall in blood pressure and pulse rate. , The extent of fall depends upon the dose and adjuvant drugs used.
In our study, the HR stability was maintained more with ketamine and thiopentone than with midazolam or normal saline. Though there was a rise in HR in all the four groups, we could see that the rise was statistically insignificant in the thiopentone and ketamine groups ('P' values between 0.32 and 0.11 respectively). The HR stability was best maintained with ketamine than with thiopentone or with midazolam.
The systolic blood pressure and diastolic blood pressure along with MAP was found to decrease in all the four groups significantly following induction. The best hemodynamic stability was offered by the ketamine group. The fall in mean arterial blood pressure from baseline in the midazolam (group 2), thiopentone (group 3) and ketamine group (group 4) was 10.88%, 14.58% and 8.37% respectively. This probably was a dose dependent phenomenon.
Our data shows that the induction dose of propofol was decreased by all the study drugs. Ketamine caused the maximum decrease in the induction dose of propofol in addition to providing better hemodynamic conditions during intubation than thiopentone or midazolam which correlated with other studies. ,,,, The total induction dose of propofol was reduced significantly by 33.92% in group 2, 35.08% in group 3 and 42.69% in group 4 from that in group 1 (control) (P < 0.001).
The sympathomimetic actions of ketamine could have counter-acted the hemodynamic depression caused by propofol.  Therefore, the arterial blood pressure in group IV was minimally changed from the baseline (4%). It could be dose related too. A trend was present for pulse rate to increase after the induction in all the groups, but there was no occurrence of profound tachycardia in any group. Ketamine balances the cardiodepressant effects of propofol by its sympathomimetic cardiostimulant action and reduces the dose of propofol required for induction.  The maximum reduction in induction dose of propofol is seen with ketamine. Midazolam does not decrease the induction dose requirement of propofol as much as that produced by either thiopentone or ketamine. Thiopentone depresses the cardiovascular system itself, so it is not as capable as ketamine in balancing the cardiodepressant effects of propofol. Ketamine has the additional advantage of better hemodynamic stability.
Thus, we can safely conclude based on our findings that among the three drugs, ketamine gives the most satisfactory control of stable hemodynamic and dose reduction of propofol than midazolam, thiopentone or saline.
| References|| |
|1.||McKeating K, Bali IM, Dundee JW. The effects of thiopentone and propofol on upper airway integrity. Anaesthesia 1988;43:638-40. |
|2.||Pensado A, Molins N, Alvarez J. Haemodynamic effects of propofol during coronary artery bypass surgery. Br J Anaesth 1993;71:586-8. |
|3.||Claeys MA, Gepts E, Camu F. Haemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 1988;60:3-9. |
|4.||Ben-Shlomo I, Finger J, Bar-Av E, Perl AZ, Etchin A, Tverskoy M. Propofol and fentanyl act additively for induction of anaesthesia. Anaesthesia 1993;48:111-3. |
|5.||Naguib M, Sari-Kouzel A. Thiopentone-propofol hypnotic synergism in patients. Br J Anaesth 1991;67:4-6. |
|6.||Cressey DM, Claydon P, Bhaskaran NC, Reilly CS. Effect of midazolam pretreatment on induction dose requirements of propofol in combination with fentanyl in younger and older adults. Anaesthesia 2001;56:108-13. |
|7.||Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J. Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 1995;82:641-8. |
|8.||McClune S, McKay AC, Wright PM, Patterson CC, Clarke RS. Synergistic interaction between midazolam and propofol. Br J Anaesth 1992;69:240-5. |
|9.||Grounds RM, Twigley AJ, Carli F, Whitwam JG, Morgan M. The haemodynamic effects of intravenous induction. Comparison of the effects of thiopentone and propofol. Anaesthesia 1985;40:735-40. |
|10.||Srivastava U, Sharma N, Kumar A, Saxena S. Small dose propofol or ketamine as an alternative to midazolam co-induction to propofol. Indian J Anaesth 2006;50:112-4. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]