Table of Contents  
Year : 2015  |  Volume : 8  |  Issue : 3  |  Page : 341-348

Bispectral index-guided induction of anesthesia by ketofol infusion provides the same cardiovascular stability like that of etomidate infusion

Department of Anesthesia, Faculty of Medicine, Ain-Shams University, Cairo, Egypt

Date of Submission09-Nov-2014
Date of Acceptance14-Apr-2015
Date of Web Publication29-Jul-2015

Correspondence Address:
Hesham F Soliman
Alnoor Specialist Hospital, PO Box 6251, Makkah 21955, Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7934.159004

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Various techniques have been tried to maintain cardiovascular stability with anesthesia induction. This study compares the cardiovascular effects of propofol-ketamine mixture versus etomidate during the induction of anesthesia.
Materials and methods
A total of 50 patients undergoing elective surgeries were randomly assigned according to the induction agents into two groups: group K (n = 25) received propofol-ketamine mixture (ketofol), and group E (n = 25) received etomidate, both by bispectral index (BIS) guidance. Mean arterial pressure (MAP), cardiac output (CO), heart rate, and systemic vascular resistance (SVR) were measured 6 min preintubation and up to 16 min postintubation. P-value less than 0.05 was considered statistically significant.
MAP and SVR were significantly increased (P < 0.001) in both groups immediately and up to 4 min postintubation compared with baseline, whereas CO and stroke volume (SV) remain unchanged. Meanwhile, there was no significant difference between both groups with regard to CO, MAP, SVR, heart rate, and BIS at each time intervals.
BIS-guided/induction by propofol-ketamine mixture is effective as etomidate in maintaining cardiac stability; however, both techniques did not prevent any hemodynamic changes as hypotension and hypertension preintubation and postintubation, respectively.

Keywords: bispectral index, etomidate, hemodynamics, intubation, ketofol, propofol, induction of anesthesia

How to cite this article:
Soliman HF. Bispectral index-guided induction of anesthesia by ketofol infusion provides the same cardiovascular stability like that of etomidate infusion . Ain-Shams J Anaesthesiol 2015;8:341-8

How to cite this URL:
Soliman HF. Bispectral index-guided induction of anesthesia by ketofol infusion provides the same cardiovascular stability like that of etomidate infusion . Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 Oct 22];8:341-8. Available from:

  Introduction Top

Hemodynamic changes usually occur during the induction of anesthesia by either intravenous induction agents or endotracheal intubation. Several studies had been conducted to compare the hemodynamic effects of propofol and etomidate, but it lacks monitoring the anesthetic depth, which has a relation with hemodynamic measurements of the cardiac parameters in those trials that might give explanation for these circulatory changes [1],[2],[3],[4],[5],[6],[7],[8] .

Induction of anesthesia with propofol is associated with significant blood pressure reduction and hemodynamic instability, especially in geriatric patients [9] . Patients with hypotension and those with American Society of Anesthesiologists' physical status (ASA)>II are more vulnerable to marked drop in blood pressure with propofol induction [10] . In addition to its amnesic and analgesic properties, ketamine increases heart rate (HR) and blood pressure by activating the sympathetic nervous system [11] . It was observed that a combination of ketamine and propofol reduced consumption of propofol and opioids and ensured better hemodynamic and respiratory stability [12],[13],[14] .

Etomidate produces less cardiovascular depression than other commonly used induction agents such as thiopentone Na and propofol. They are considered the induction agents of choice for high-risk patients with cardiorespiratory diseases, and for that reason they have also been used for laryngeal mask insertion [15] . The aim of this study is the assessment of the cardiovascular effects such as mean arterial pressure (MAP), HR, systemic vascular resistance (SVR), SV, and cardiac output (CO) of ketofol and etomidate infusions during the induction of anesthesia and tracheal intubation. It was suggested that bispectral index (BIS)-guided titration of both anesthetics might reduce the required dose and alleviate the negative cardiovascular effects.

  Materials and methods Top

This prospective randomized double-blinded trial was conducted in Al-Noor Specialist Hospital, Makkah, Saudi Arabia, from February 2013 to March 2014.

After approval from the Research and Ethics Committee, 55 patients were screened for eligibility to participate in the study. Written informed consent was obtained from 50 patients with age of 18-60 years, both sex, American Society of Anesthesiologists' physical class I or II patients, and scheduled for elective surgery.

Patients with BMI above 30, allergic to study medications, anticipated difficult airway, intubation failed once or intubation time exceeded 20 s, psychiatric illness, language barrier and patients on β-blockers, α-blockers, or sympathomimetics were excluded from the study. No premedications were offered. In the operating theater, standard monitoring was applied in the form of noninvasive blood pressure, ECG, and pulse oximetry (Drager, Primus, Dräger Medical GmbH, Lübeck, Germany). Patients' foreheads were prepared with alcohol swap followed by BIS electrode application (Covidien, Lake Forest, IL, Massachusetts, USA). For noninvasive cardiovascular parameter measurements, a cuff sensor applied to the patients' index and middle fingers that was connected to a monitor, which displayed beat to beat MAP, HR, SVR, SV, and CO (CNAP monitor 500 HD; CNsystems Medizintechnik AG, Graz, Austria) [Figure 1]. Baseline measurements were recorded and, 1 min after, fentanyl (fentanyl; Janssen-Cilag Pharma, Turnhoutseweg 30, B-2340 Beerse, Belgium) 2 μg/kg was administered intravenously. Two minutes later, the induction of anesthesia was started. The patients were randomized by a computer-generated random list enclosed in opaque envelopes to one of two groups. The ketofol group (group K; n = 25) received a drug mixture of 20 ml of ketamine 10 mg/ml (Ketam 10; Hekma Pharmaceutical, Amman, Jordan) with 20 ml propofol 1% (Fresenius Kabi, Bad Homburg, Germany) to constitute 40 ml mixture of 5 mg/ml for each drug, which was infused during induction at a rate of 0.5 mg/kg/min, whereas the etomidate group (group E; n = 25) received etomidate (hypomidate; Janssen, Beerse, Belgium) prepared as 2 mg/ml concentration in 40 ml volume, which was infused during induction at a rate of 0.05 mg/kg/min. The study medications were prepared by independent contributor in 50 ml syringes (the perfusor, Alaris CC for 50 ml syringe; Cardinal Health, Dublin, Ireland) covered by aluminum paper and loaded in syringe pump (Fresenius vial, Module DPS + IS3; La Grande Chamin, Brezins, France).
Figure 1: CNAP monitor

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After loss of eyelash reflex and BIS values reach 60, the anesthetic drug infusion was stopped, and rocuronium 0.6 mg/kg (Esmeron; NV Organon, Oss, the Netherlands) was administered intravenously, followed by manual ventilation of the patients' lungs for 1 min, and patients' tracheas were intubated by the examiner, who was blinded to the study medications. The independent contributor recorded a total consumed dose of each anesthetic agent, the time for eye lash reflex loss, time to BIS 60 and intubation time that was measured from the passage of the laryngoscope blade patients' incisors to appearance of the displayed end-tidal CO 2 . After intubation, the patients' lungs were mechanically ventilated with sevoflurane 1 vol% in oxygen and air mixture (1: 1), 3 l/min fresh gas flow and minute ventilation was adjusted to maintain normocapnia. Cardiovascular and BIS values were recorded at −6 min (baseline), −4 min, −1 min, 0 min (intubation), 1 min, 4 min, 7 min, 10 min, 13 min, and 16 min postintubation. End-tidal CO 2 (EtCO 2 ) and end-tidal sevoflurane (ET Sevo) were recorded at 1 and 5 min after intubation. Complications were planned to be recorded and treated as follows: hypotension (MAP ≤55 mmHg) treated with phenylephrine 1 μg/kg incremental doses until the desired clinical effect was achieved. Hypertension (MAP ≥100 mmHg) and tachycardia (HR ≥90/min) were treated with fentanyl 1 μg/kg. Bradycardia (HR ≤40/min) was treated with atropine 0.5 mg.

Statistical methods

The required sample size was calculated using the G*Power software version 3.1.7 (Moorenstraße 5, 40225 Düsseldorf, Germany). The primary outcome measures were the differences between the two groups with regard to the hemodynamic measures and the BIS. The secondary outcome measures were the dose of ketofol, etomidate, and the end-tidal sevoflurane concentration. It was estimated that a sample of 25 patients in either study group would achieve a power of 80% to detect a statistically significant difference between the two groups for a large effect size of d = 0.8. This calculation used the unpaired t-test and assumed a two-sided type I error of 0.05. An effect size of d = 0.8 was chosen as it could be regarded as a clinically relevant difference to seek in this exploratory study.

Data were analyzed using IBM© SPSS© Statistics version 22 (IBM© Corp., Armonk, New York, USA) and MedCalc© version 13 (MedCalc© Software bvba, Ostend, Belgium). The D'Agostino-Pearson test was used to examine the normality of numerical data distribution. Normally distributed numerical variables were presented as mean and SD, and intergroup differences were compared using the independent samples (unpaired) t-test. The paired t-test was used for within-group comparison of paired measures.

Repeated-measures analysis of variance was used to analyze serial measurements. Repeated measures were compared with baseline values using the Bonferroni test.

Mixed-linear modeling was used to examine the effect of time, randomization group, and time-group interaction on the percent change in the outcome measures from baseline.

A two-sided P-value less than 0.05 was considered statistically significant.

  Results Top

The flow of patients throughout the trial is shown in [Figure 2]. No significant differences between the two groups with respect to patient characteristics, hemoglobin level and intubation time [Table 1]. There were no significant differences between both groups regarding the time to loss of eyelash reflex (120.5 ± 10.8 s in group K versus 120.0 ± 10.3 s in group E, P = 0.862), and time to reach BIS of 60 (136.0 ± 12.1 s in group K vs. 135.3 ± 11.2 s in group E, P = 0.838) [Table 1]. In the postinduction and preintubation period, MAP, SVR, and BIS decreased significantly compared with baseline values in both groups, whereas CO and SV remained almost unchanged [Table 2] [Table 3] [Table 4] and [Figure 3], [Figure 4]. With intubation, MAP and SVR were significantly increased (P < 0.0001) in both groups and remained significantly high up to 4 min after intubation in comparison with baseline, whereas CO and SV remain almost unchanged. However, there was no significant difference between both groups with respect to CO, SV, MAP, SVR, HR, and BIS at each time interval [Table 2] [Table 3] [Table 4] and [Figure 3], [Figure 4]. Mixed-linear modeling for the percent variation from baseline in hemodynamic measures and BIS [Table 5] showed that except for the CO (P = 0.001), there was no significant difference between the two groups with regard to the trend in the percent change from baseline for the MAP (P = 0.590), HR (P = 0.079), SV (P = 0.824), SVR (P = 0.685), and BIS (P = 0.261). No anesthetic complications such as hypotension or bradycardia were recorded. There was no significant difference between both groups with respect to end-tidal CO 2 at 1 and 5 min postintubation [P = 0.930 and 0.377, respectively [Table 5]]. In addition, there was no significant difference between both groups with respect to end-tidal sevoflurane % at 1 and 5 min postintubation (P = 0.541 and 0.726) [Table 6]. The mean consumed anesthetic doses were 0.97 ± 0.1 mg/kg of either propofol or ketamine in group K and 0.14 ± 0.01 mg/kg for group E [Table 6].
Figure 2: CONSORT flow chart showing flow of patients through the trial

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Figure 3: Change in hemodynamic variables and bispectral index (BIS) in both study groups. Error bars represent 95% confidence int erval (CI).

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Figure 4: Percent change from baseline in hemodynamic variables and bispectral index (BIS) in both study groups. Error bars represent 95% confidence int erval (CI).

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Table 1: Patients' characteristics and details of the induction of anesthesia and intubation in both groups

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Table 2: Change in mean arterial pressure and heart rate in both groups

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Table 3: Change in cardiac output in both groups

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Table 4: Changes in systemic vascular resistance and bispectral index in both groups

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Table 5: Mixed linear modeling for the percent variation from baseline in hemodynamic measures and bispectral index

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Table 6: Change in end-tidal carbon dioxide and sevoflurane concentration in both groups

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  Discussion Top

The use of propofol-ketamine mixture for the induction of anesthesia maintained the cardiovascular stability and reduced the required dose of both drugs to achieve adequate depth of anesthesia. Administration of ketamine and propofol mixed in the same syringe (so-called ketofol) has been proved to be effective in providing adequate sedation in day-care surgeries [16],[17],[18] .

The hemodynamic stability associated with etomidate makes it the drug of choice for induction in hypotensive patients, as well as an attractive option for patients with intracranial pathology for which hypotension should be avoided [19],[20],[21],[22],[23] . However, etomidate causes primary adrenal suppression owing to reversible inhibition of 11-β-hydroxylase enzyme essential for adrenal steroid production [24] . The cortisol suppression induced by a single dose of etomidate is almost temporary and limited to 24 h [25],[26] .

The influence of BIS-guided infusion of etomidate and ketofol on hemodynamics before, during, and after tracheal intubation in patients undergoing elective surgery was studied. The time frame of the study (−6 to 16 min after intubation) was selected on the basis of already described pharmacokinetics and pharmacodynamics of the study drugs and timing related to surgical stimulation that might affect hemodynamics [27],[28],[29],[30] .

Noninvasive CO, SV, and SVR measurements are used nowadays on a big scale than invasive ones owing to lower risk of complications. CNAP monitor provides accurate beat-to-beat measurement of CO, MAP, SV, and SVR by analyzing the arterial blood pressure tracing without arterial cannulation [31],[32],[33] .

The aim of infusion technique of induction agents to BIS 60 in the present study was to decrease the total dose of induction agents with subsequent decrease in hemodynamic attenuation. The BIS monitor is validated for measuring the depth of anesthesia [34],[35] . Ketofol has been used as bolus to provide sedation and analgesia for painful procedures in the emergency room [36] and as infusion to provide anesthesia for coronary artery surgery [37] . A study by Aouad et al. [38] reported that addition of ketamine to propofol for procedural anesthesia in children has reduced propofol and fentanyl consumption with maintenance of hemodynamics. The present study showed that ketofol infusion resulted in reduction of both propofol (0.97 ± 0.11 mg/kg) and ketamine (0.97 ± 0.11 mg/kg) doses required to achieve adequate depth of anesthesia, which comes in agreement with the results of studies conducted by Guit et al. [12] and Gray et al. [13] .

Several trials were conducted for comparison between induction of anesthesia by etomidate by bolus versus infusion method in which the latter method was superior to the former in decreasing consumption of anesthetics and achievement of better hemodynamic stability, which agrees with the results of the present study [27],[39] . The infusion speed of anesthetics used in the present study was based on previous trials [28],[40],[41] .

In the current study on preintubation, there were no changes in SV and CO, whereas a decrease in MAP in both groups was noticed. This decrease in MAP may be attributed to attenuation of the vasomotor tone proved by a significant decrease in SVR that might be caused by the concomitant administration of fentanyl. Postintubation, MAP and SVR increased significantly in both groups and remained significantly high up to 4 min with respect to baseline, whereas CO and SV remain almost unchanged. The elevation of MAP and SVR during intubation might be because of the pressor response of intubation. However, it did not require interference in any patient as per the study protocol. Stability of CO and SV is observed in the present study, despite decrease in MAP before intubation and its increase during and after intubation that may be owing to the BIS-guided infusion of induction agents technique used, which allowed smaller total anesthetic dose. In the study, no hemodynamic complications occurred in any patient necessitating interference. Möller Petrun and Kamenik [42] compared BIS-guided induction of anesthesia by etomidate and propofol as they reported significant increase in MAP and cardiac index in the etomidate group and significant decrease in MAP in propofol group with 50% of patients developed hemodynamic instability. On the contrary, the current study revealed hemodynamic stability with adding ketamine to propofol as the former might attenuated the cardiovascular depressant effect of propofol. In addition, in their study, they included patients with ASA III classification, whereas in the present study only ASA I, II patients were selected. Similar to the present study, a study by Khutia et al. [43] also concluded that combination of ketamine and propofol is more safe and an effective sedative analgesic regimen than the combination of propofol and fentanyl in pediatric emergency and short surgical procedures in terms of hemodynamic stability and less incidence of apnea. Bendel et al. [44] performed BIS-guided anesthesia induction in patients with aortic stenosis using either propofol or etomidate infusion where propofol was found to induce hypotension as twice as did etomidate. Lallemand et al. [45] studied the effect of different bolus doses of etomidate (0.2, 0.3, and 0.4 mg/kg) on patients' hemodynamics with no significant differences. The present study did not include patients with ASA classification³III and older than 60 years for which further study is recommended to assess the cardiovascular response on such patients' status. The present study used fentanyl in a dose of 2 μg/kg that might have affected the measured cardiovascular parameters. Further studies need to be conducted using ketofol and etomidate, each as a single anesthetic agent without addition of fentanyl.

  Conclusion Top

BIS-guided induction of anesthesia with either ketofol or etomidate infusion were effective in maintaining overall cardiovascular stability and reduced the total induction doses of both anesthetic agents. However, both techniques did not prevent some hemodynamic changes such as preintubation hypotension, despite titration of anesthetic agents to an appropriate anesthesia depth.

  Acknowledgements Top

Conflicts of interest

None declared.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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