Efficacy of Ketofol in Blunting Hypotensive Effects of Propofol during Induction and Its Effect on Intraoperative Anesthetic Requirements and Recovery Profile.

BACKGROUND: Major disadvantage of propofol is dose-dependent hypotension. AIM OF THE STUDY: The aim of the study was comparison of changes in heart rate (HR) and mean arterial pressure (MAP) after induction with propofol versus ketofol (a combination of ketamine and propofol). SETTINGS AND
DESIGN: This was a prospective randomized study conducted in a tertiary care institute. SUBJECTS AND METHODS: Sixty patients were recruited. Group A patients were induced with 1.5-2.5 mg.kg-1 propofol. In Group B, ketamine 1 mg.kg-1 was given intravenously followed by propofol 1-2 mg.kg-1. All patients received standardized intraoperative management. STATISTICAL TESTS USED: Chi-square test, independent sample t-test, and paired t-test were used for statistical analysis.
RESULTS: Baseline HR and HR immediately after induction were comparable in both groups. There was a significant decrease in mean HR at 3 min postinduction in Group A compared to Group B (65.7 ± 5.4 vs. 80.8 ± 12.4). At 1 min postintubation, there was a significant rise in HR in Group A (103.5 ± 12.4 vs. 84.8 ± 9.5). HR remained comparable in both groups at other timelines. Baseline MAP was comparable between groups. Mean MAP in Group A was significantly lower than Group B immediately after induction and at 3 min postinduction. MAP was significantly higher in Group A at 1 min postintubation and remained comparable at other time points. The incidence of hypotension was significantly higher in Group A compared to Group B.
CONCLUSION: Combining ketamine 1 mg.kg-1 to propofol blunted hypotensive and bradycardic effects of propofol. Ketofol effectively attenuated hemodynamic responses to intubation and was associated with reduced intraoperative opioid consumption with no added risks of excessive postoperative sedation or emergence delirium. Copyright:

INTRODUCTION

Hypotension following induction of general anesthesia is common[1] and is more prevalent in the first 10 min postinduction. Persistent hypotension following induction may have significant effects in high-risk patients as it can present as stroke, myocardial injury, or acute kidney injury, resulting in postoperative morbidity, mortality, and long-term intensive care unit stay.[234]

Major disadvantage of propofol is dose-dependent hypotension.[56] Ketamine administration is usually associated with hypertension and tachycardia due to its sympathomimetic effects.[7] By combining both propofol and ketamine, due to additive anesthetic effects, the dose of each drug could be reduced for induction and the adverse cardiovascular effects of both the agents could be nullified.

The primary objective of the study was to compare the changes in heart rate (HR) after induction of general anesthesia with propofol versus ketofol, a combination of ketamine and propofol, in patients undergoing surgical procedures. The secondary objectives included comparison of changes in mean arterial pressure (MAP), incidence of hypotension or hypertension after induction, time taken for loss of verbal response, level of sedation at the time of extubation, presence or absence of emergence delirium at the end of surgery, dose of propofol required for induction of general anesthesia, and intraoperative fentanyl consumption following induction with propofol and ketofol.

SUBJECTS AND METHODS

This prospective, randomized single-blinded study was conducted after obtaining approval from the Institutional Ethics Committee (IEC-AIMS-2020-ANES-047 dated May 11, 2020). Informed consents from patients were obtained for participation in the study and the use of the patient data for research and educational purposes. The study was registered in the Clinical Trials Registry of India (CTRI/2020/05/025380). Sixty patients aged 18–65 years, of American Society of Anesthesiologists Physical status (ASA PS) 1–3, having Mallampatti (MP) score 1 and 2, and undergoing surgeries lasting for 2–3 h were included. Those with anticipated difficult airway, psychiatric illness, significant cardiac diseases, and history of emergence delirium and those on rate controlling drugs were excluded. Study procedures followed the guidelines laid down in the Declaration of Helsinki.

Based on mean and standard deviation (SD) of HR (67.25 ± 3.98) in propofol group and (78.05 ± 5.20) in ketofol group observed in an earlier publication by Abdoeldahab et al.,[8] with 90% power and 99.9% confidence, the minimum sample size required to obtain statistically significant results was calculated to be 8 per group. However, we recruited 30 cases per group during the study period of 6 months.

Following a detailed preanesthetic evaluation, all patients were orally premedicated with alprazolam 0.5 mg and metoclopramide 10 mg at night before surgery and were kept fasting 6 h for solids and 2 h for clear fluids. Patients were randomly allotted to Group A or Group B based on computer-generated random sequence of numbers. Allocation concealment was ensured using sequentially numbered opaque-sealed envelopes.

In the operation theater, patients were hydrated with intravenous (i.v.) Ringer lactate at a rate of 10 mL.kg−1 body weight. Preinduction monitors such as electrocardiogram, noninvasive blood pressure monitor, and pulse oximeter were attached. All patients received midazolam 2 mg, fentanyl 2 μg.kg−1, and glycopyrrolate 0.2 mg intravenously. Patients in both groups were preoxygenated for 3 min. Group A patients were induced with 1.5–2.5 mg.kg−1 propofol given over 30 s till there was loss of response (LOR) to verbal commands. In Group B, ketamine 1 mg.kg−1 was given intravenously followed by propofol 1–2 mg.kg−1 over 30 s till there was LOR to verbal commands.

The time taken for induction was calculated as time from administration of the induction agent till LOR to verbal command, which was noted by an anesthesia technician. After ensuring mask ventilation, all patients were given vecuronium 0.1 mg.kg−1 i.v. and ventilated with 1% isoflurane in oxygen. At 3 min, a gentle and short laryngoscopy, not lasting for 15 s, was performed and trachea was intubated with an 8.0 mm cuffed endotracheal tube in males and with a 7.0 mm internal diameter endotracheal tube in females. Correct placement of the endotracheal tube was confirmed with auscultation and appearance of regular end-tidal carbon dioxide (EtCO2) wave forms.

Patients were maintained with isoflurane 1%–1.5% in oxygen–air mixture (1:1), with mechanical ventilation with tidal volume 6–8 mL.kg−1, respiratory rate of 12–14 per minute maintaining EtCO2 between 30 and 35 mm of Hg. HR, systolic blood pressure, and MAP were recorded before induction of anesthesia, immediately after induction, 3 min after induction, and then at 1, 3, 5, and 10 min after intubation.

Reduction in MAP more than 20% from baseline value was taken as hypotension and was treated with 250 mL i.v. fluid bolus; if not responding, incremental dose of phenylephrine 50 μg was given. If increase in HR did not respond or was associated with increase in MAP more than 20% from baseline, it was initially managed with increasing isoflurane to 2%. If still not responding, incremental boluses of fentanyl, not exceeding 0.5 μg.kg−1 body weight, was given to a maximum of 1 μg.kg−1 bodyweight in 1 h.

At end of the surgery, the level of sedation was assessed using Ramsay sedation score (RSS) at 10 min and 30 min after extubation. Presence or absence of excitation delirium was also noted following extubation. Total propofol and intraoperative fentanyl consumption was also noted.

Statistical analysis

Categorical variables are presented as number and percentage and continuous variables as mean and SD. Chi-square test was used to compare the categorical variables and independent sample t-test to compare continuous variables of Group A and Group B. Paired t-test was used to compare the HR and MAP at different time points from the baseline within groups. Statistical analyses were conducted using SPSS Version 20.0 for Windows (IBM Corporation Armonk, NY, USA).

RESULTS

Data of 60 patients were analyzed [Figure 1]. Mean age, weight, distribution of gender, ASA PS, and MP score were comparable in both groups. Baseline HR and that immediately after induction were comparable in both the groups. There was a significant decrease in mean HR at 3 min postinduction in Group A compared to Group B (65.7 ± 5.4 vs. 80.8 ± 12.4 min, P < 0.001). At 1 min postintubation, there was a significant rise in mean HR in Group A compared to Group B (103.5 ± 12.4 vs. 84.8 ± 9.5, P < 0.001). The HR remained comparable in both the groups at all other timelines [Table 1].

Figure 1

CONSORT flow diagram

Table 1

Comparison of mean heart rate between groups

Time	Mean±SD		P
	Group A	Group B
Baseline	84.7±11.9	81.1±9.7	0.209
Immediate postinduction	79.2±8.6	82.2±11.3	0.257
3 min	65.7±5.4	80.8±12.4	<0.001
1 min postintubation	103.5±12.4	84.8±9.5	<0.001
3 min	94.1±8.9	88.0±15.8	0.073
5 min	86.9±9.4	84.6±15.4	0.499
10 min	81.3±9.9	82.2±15.0	0.793

SD=Standard deviation

Group A showed a significant decrease in HR from baseline immediately after induction and at 3 min after induction. There was significant rise in HR from baseline at 1 and 3 min postintubation. HR at all other time intervals was comparable with baseline. In Group B, there was a significant rise in HR from baseline at 1 and 3 min postintubation (P = 0.022). HR at all other time intervals remained comparable with baseline [Table 2].

Table 2

Intragroup analysis of changes in heart rate from baseline

Time	Mean±SD	P
Comparison of HR with baseline in Group A
Baseline	84.7±11.9
Immediate postinduction	79.2±8.6	0.005
3 min	65.7±5.4	<0.001
1 min postintubation	103.5±12.4	<0.001
3 min	94.1±8.9	<0.001
5 min	86.9±9.4	0.319
10 min	81.3±9.9	0.146
Comparison of HR with baseline in Group B
Baseline	81.1±9.7
Immediate postinduction	82.2±11.3	0.378
3 min	80.8±12.4	0.822
1 min postintubation	84.8±9.5	0.014
3 min	88.0±15.8	0.022
5 min	84.6±15.4	0.244
10 min	82.2±15.0	0.720

SD=Standard deviation, HR=Heart rate

Baseline mean MAP was comparable between the groups. Mean MAP in Group A was significantly lower than Group B immediately after induction and at 3 min postinduction. MAP was significantly higher in Group A at 1 min postintubation and remained comparable at other time points [Table 3].

Table 3

Comparison of mean arterial pressure between the groups

Time	Mean±SD		P
	Group A	Group B
Baseline	95.6±11.8	94.6±9.1	0.727
Immediate postinduction	83.6±11.7	90.4±8.8	0.013
3 min	70.1±6.8	85.2±8.0	<0.001
1 min postintubation	101.4±13.1	92.7±7.7	0.003
3 min	90.4±14.2	89.2±6.5	0.685
5 min	85.3±14.7	89.2±6.2	0.198
10 min	83.5±14.5	88.1±6.0	0.112

SD=Standard deviation

Intragroup analysis in Group A showed a significant reduction immediately after induction, at 3 min postinduction, and at 3, 5, and 10 min postintubation when compared to baseline. However, the mean MAP at 1 min postintubation was significantly higher compared to the baseline. In Group B, MAP was significantly lower immediately after induction, 3 min postinduction, and at 3, 5, and 10 min postintubation. However, the difference in MAP was not statistically significant at 1 min postintubation when compared to baseline [Table 4].

Table 4

Intragroup analysis of changes in mean arterial pressure from baseline

Time	Mean±SD	P
Comparison of MAP with baseline in Group A
Baseline	95.6±11.8
Immediate postinduction	83.6±11.7	<0.001
3 min	70.1±6.8	<0.001
1 min postintubation	101.4±13.1	0.010
3 min	90.4±14.2	0.054
5 min	85.3±14.7	0.002
10 min	83.5±14.5	<0.001
Comparison of MAP with baseline in Group B
Baseline	94.6±9.0
Immediate postinduction	90.3±8.7	0.004
3 min	85.2±7.9	<0.001
1 min postintubation	92.6±7.6	0.235
3 min	89.2±6.4	0.003
5 min	89.1±6.1	0.007
10 min	88.1±5.9	0.002

SD=Standard deviation, MAP=Mean arterial pressure

The time taken for LOR to verbal commands was comparable in both groups (39.8 ± 12.6 s and 42.6 ± 9.8 s). Propofol consumption was significantly higher in Group A (140.7 ± 29.7 vs. 79.7 ± 18.7 mg, P < 0.001). The intraoperative fentanyl consumption was significantly higher in Group A compared to Group B (142.8 ± 26.3 vs. 127.3 ± 19.3 μg). Interventions with i.v. fluid boluses and vasopressors as well as RSS at 10 and 30 min were comparable in both the groups.

The incidence of hypotension was significantly higher in Group A compared to Group B [60% vs. 10%, P < 0.001]. The incidence of tachycardia and hypertension was higher in Group A compared to Group B (40% vs. 10%, P = 0.015). Fall in HR <20% from baseline was seen in 60% of the patients in Group A and 20% of the patients in Group B which was statistically significant [P = 0.003, Table 5].

Table 5

Comparison of hemodynamic variations

Variables	Group A, n (%)	Group B, n (%)	P
Hypotension	18 (60)	3 (10)	<0.001
Tachycardia	12 (40)	3 (10)	0.015
Hypertension	12 (40)	3 (10)	0.015
HR <20% from baseline	18 (60)	6 (20)	0.003

HR=Heart rate

DISCUSSION

Although various i.v. agents had come into anesthetic practice, very few lasted the test of time. The agent that was used for decades was thiopentone. Its initial popularity was due to its apparently shorter duration of action and faster awakening. However, with the advent of propofol, an agent with much shorter duration of action and better emergence profile, the use of thiopentone started to decline. However, the major concerns with propofol, profound hypotension and bradycardia following induction, remain unresolved. Different methods have been employed with variable results to counter the hypotensive effects of propofol, such as slow administration of the drug,[8] preloading with i.v. fluids,[9] and co-administration of ephedrine[910] and phenylephrine.[11]

Use of ketamine, the induction agent with least potential for hypotension, is limited due to its accelerated cardiovascular stimulant effects and emergence delirium. Ketofol, a combination of propofol and ketamine, was introduced into anesthetic practice with the main aim of overcoming side effects of both agents and attaining optimal hemodynamic effects after induction. Various concentrations of each drug was tested but with varying results.

In our study, we had observed a reduction in HR and blood pressure following induction with propofol as in many previous studies.[56] We also observed that combining ketamine to propofol effectively reduced the incidence and severity of hypotension and bradycardia compared to induction with propofol alone. Similar observations were made by Abdoeldahab et al.[8] and Phillips et al.[12]

Most researchers earlier had used precalculated doses of ketamine and propofol such as 0.75 mg.kg−1 ketamine and 0.75 mg.kg−1 propofol,[13] propofol 1 mg.kg−1 followed by 0.5 mg.kg−1 ketamine,[14] and propofol 1.5 mg.kg−1 and ketamine 0.5 mg.kg−1.[15] Propofol and ketamine in the ratio 1:1,[8] propofol and ketamine at 0.75 mg.kg−1 body weight,[12] propofol 1.6 mg.kg−1 body weight, and ketamine 0.4 mg.kg−1 body weight were also used.

The end point of induction in our study was LOR to verbal commands, which was attained by an initial administration of a fixed dose of ketamine followed by titrated doses of propofol. This practice allowed use of minimum dose of propofol to attain desired anesthetic depth, thereby helping to reduce dose-related side effects of propofol. This was a major difference which could be pointed out with most of the previously published studies. When fixed doses of test drugs are used, titration of individual drugs becomes impossible and hence ability to reduce dose-related side effects could be eliminated. The mean propofol requirement in our study was 1.31 mg.kg−1 body weight in the ketofol group.

Combining ketamine with propofol helps overcome hypotension of propofol induction[1617] as the positive chronotropic and inotropic effects of ketamine nullify the hypotensive effect of propofol. Another factor important is the speed of injection of propofol. We administered propofol over 30 s till there was loss of verbal response. In a previous trial by Abdoeldahab et al.,[8] propofol was administered over 20 s. The slower administration of propofol allowed us better titration so that only optimum dose of propofol was administered. Therefore, hypotension followed by rapid injection of propofol was prevented to a certain extent. Maintenance of HR in the ketofol group could be because of use of lower dose of propofol and also secondary to positive chronotropic effects of ketamine.

We found that the requirement of additional fentanyl was higher in the propofol group intraoperatively compared to the ketofol group. Similar observation was made in previous studies.[1517] This could be attributed to the intense analgesic properties of ketamine, even in subanesthetic plasma concentrations. The absence of analgesic properties of propofol is presumably the reason for the higher intraoperative opioid consumption in the group which received only propofol for induction.

Hypertension following laryngoscopy and intubation requiring additional doses of propofol was lesser in the ketofol group compared to the propofol alone group in our study; similar observations were made by Akin et al.[15] and Bhaire et al.[17] Anesthetic and analgesic properties of ketamine could have provided a deeper plane of anesthesia obtunding stress responses of laryngoscopy and intubation.

In the present study, intervention with vasopressors was required in both the groups but with no significant difference among the groups. Contradicting results were documented earlier,[17] where patients in the propofol group required significantly more interventions with vasopressors to treat hypotension than the ketofol group. The comparable requirement of vasopressors in both groups in our study could be due to use of lesser doses of propofol, adequate hydration, and slower administration of propofol during induction.

The common reservation in using ketamine is its preponderance in causing emergence delirium, especially in young adults. Another concern with the use of ketamine is excessive sedation postoperatively. We did not observe occurrence of delirium or excessive postoperative sedation following ketamine administration in our study, probably because of use of a lower dose, single bolus administration just at the beginning of surgery, and also longer duration of surgery.

The major drawback of our study was it being a single-blinded study. Although ketamine is known to cause emesis and propofol being an antiemetic, the incidence and severity of postoperative nausea and vomiting were not assessed. Patients undergoing different types of surgeries were included in our study. Hence, patients might have had varying degrees of surgical stimuli which might have influenced intraoperative analgesic requirements.

CONCLUSION

It is concluded that combining ketamine 1 mg.kg−1 body weight to propofol for induction of general anesthesia blunted the hypotensive and bradycardic effects of propofol. Ketofol effectively attenuated hemodynamic responses to laryngoscopy and intubation. Its use was associated with reduced intraoperative opioid consumption with no added risks of excessive postoperative sedation or emergence delirium.

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Nil.

Conflicts of interest

There are no conflicts of interest.