TITLE: 
Comparison of ketamine with fentanyl as co-induction in propofol anesthesia for short surgical procedures



ABSTRACT.BACKGROUND AND OBJECTIVE:
A prospective randomized control study was conducted to compare and evaluate quality of anesthesia with ketamine or fentanyl as co-induction with propofol.

ABSTRACT.MATERIALS AND METHODS:
Sixty ASA I or II, 18–50 year old patients who were scheduled for minor surgeries of short duration (<30 min anticipated duration) were selected. The patients were randomly allocated to group I and group II comprising 30 patients each. The patients of group I were given ketamine injection 0.5 mg/kg and group II patients fentanyl injection (1.5 μg/kg) as co-induction agent. Two minutes later, induction of anesthesia was given with inj propofol (2.5 mg/kg) and appropriate-sized laryngeal mask airway was inserted. The anesthesia was maintained with 60% N2O in O2 and intermittent bolus of inj propofol (0.5 mg/kg) after observing significant changes in the heart rate, blood pressure, lacrimation, sweating, and abnormal movements.

ABSTRACT.RESULTS:
There was significant decrease (P<0.05) in the pulse rate, systolic and diastolic blood pressure at 1, 3, and 5 min in group II (fentanyl group) whereas the change was insignificant (P>0.05) at 10 min.

ABSTRACT.CONCLUSION:
It was observed that ketamine as premedicant was better than fentanyl with respect to hemodynamic stability and caused less adverse effects intraoperatively and postoperatively.

BODY.INTRODUCTION:
Recently, the concept of co-induction has been proved better in various anesthetic procedures. The rationale behind co-induction is that drug combination produces desired effects in more appropriate and balanced manner with fewer side effects that can be observed by using single drug. Most often fentanyl has been used as co-induction agent with propofol.[1] Ketamine in subanesthetic dose has also gained attention as an alternative analgesic as well as the co-induction agent.[2] The aim of this study was to compare ketamine with fentanyl as premedicant in propofol anesthesia with respect to hemodynamic changes and intraoperative or postoperative adverse effects.

BODY.MATERIALS AND METHODS:
After approval from departmental ethical committee, sixty patients of ASA I or II, aged between 18 and 50 years of either sex, undergoing minor surgeries (anticipated duration of surgery <30 min) were randomly selected for this prospective double blind study. Informed consent was obtained from all patients. The patients with history of hypertension, convulsions, psychiatric disorders, hepatic or renal disease, and having any narcotic addiction were excluded from the study. The patients having hypersensitivity with fentanyl, propofol, and ketamine were also excluded from the study.
The patients were shifted to the operation theatre and an 18 G intravenous cannula was inserted at dorsum vein of left hand and ringer lactate was started. Intraoperative monitoring included ECG (continuous), pulse rate, noninvasive blood pressure, oxygen saturation, capnography, and temperature (using Datex AS5 monitor®).
All patients were asked to fast for 8 h before proposed time of surgery. All patients received injection glycopyrrolate 0.2 mg and injection Ondansetron 0.1 mg/kg intravenously 15 min prior to induction. The patients were randomly allocated and divided in two groups according to drug combination they received. The random numbers from computer generated random tables were written in the chits and one of the anesthesiologist who was blinded to the groups picked up the chit (using the chit-in-box technique). The patients of group I received intravenous ketamine injection 0.5 mg/kg and group II patients received fentanyl injection 1.5 μg/kg, as the co-induction agent. Two minutes later, induction of anesthesia was done with inj. propofol 2.5 mg/kg and the patients were asked to count numbers during induction. The drug was stopped as soon as patient could not count and it was further confirmed by asking the patient to open his eyes. Immediately, an appropriate-sized laryngeal mask airway (LMA) was inserted with a classic technique by an experienced anesthesiologist and anesthesia was maintained with 60% N2O in O2. The patients, where number of LMA insertion attempts increased to more than 2, were excluded from the study.
Top up doses of propofol (intermittent 0.5 mg/kg bolus) were administered when there were more than 20% changes in the baseline heart rate and blood pressure or there was lacrimation, sweating, or abnormal movements. The parameters recorded were systolic and diastolic blood pressure, pulse rate, respiratory rate, and arterial oxygen saturation at 1, 3, 5, and 10 min after induction. The temperature monitoring was done intraoperatively via nasopharyngeal route (Datex AS 5®). Postoperatively, incidence of apnoea, incidence of laryngeal spasm, recovery time, adverse effects, (nausea, vomiting, dizziness, and delirium) and awareness during procedure were noted. The nausea vomiting, dizziness, and delirium were monitored for first 4 h in postoperative room and subsequently in next 24 h.
The LMA was removed and patient was extubated at completion of surgery and the patients were given postoperative oxygenation by the facemask. Statistically, the mean age, mean weight, and intraoperative adverse events were compared using the Chi-square test and student's t-test was used for comparison of recovery time, mean systolic and diastolic blood pressure, and mean pulse rate. The Wilcoxin rank sum test was used for continuous variables and P-value of <0.05 was considered as significant. At 80% power (α=0.05), it was calculated that 30 patients in each group would be sufficient for the present study. This prospective power analysis was based on pilot cases and the previous literature.[34] To allow the potential dropout, we decided to recruit a total of 30 patients per group.

BODY.RESULTS:
The demographic profile with respect to age, weight, and sex in both groups were statistically comparable [Table 1].
Table 1Demographic profile
The types of surgical procedure were similar in two groups [Table 2].
Table 2Types of surgeries
Pain due to propofol injection and presence of abnormal movements were statistically insignificant (P>0.05) in both the groups while incidence of apnoea was more in group II (P<0.05). None of the patients experienced laryngeal spasm and pain during procedure [Table 3].
Table 3Intraoperative adverse effects
Awakening time (spontaneous eye opening) and recovery time (when patient was able to answer simple questions such as name, age, date of birth, time, and place) were statistically insignificant in both groups [Table 4].
Table 4Recovery, awakening, time, and mean total propofol doses
There was no complication observed in 86.66% patients of both groups. Ten percent patients of group II had felt nausea. Four patients of Group I and 1 patient of group II felt dizziness. Majority of patients of both groups had pleasant experience of anesthesia [Table 5].
Table 5Postoperative complications
Intraoperatively, hemodynamic variables were also compared at specific intervals after induction. There was statistically significant higher reduction in mean systolic blood pressure intraoperatively in group II at 1 and 3 min, but at 10 min it was insignificant. Mean diastolic blood pressure also showed a significant higher reduction in diastolic blood pressure at 1 and 3 min that became statistically insignificant at 5 and 10 min. Similarly, there was significant higher reduction in the mean pulse rate at 1, 3, and 5 min in group II but not at 10 min. There was no statistically significant difference in both the groups [Figures 1–3].
Figure 1Mean Systolic Blood Pressure in two groups at 1, 3, 5 and 10 minutes
Figure 2Mean Diastolic Blood Pressure in two groups at 1, 3, 5 and 10 min
Figure 3Pulse Rate in two groups at 1, 3, 5 and 10 minutes
The postoperative complications were also observed. Only four patients in group II complained of nausea, but no episode of vomiting was recorded. Four patients in group I and one in group II experienced dizziness whereas no patient in either group complained of delirium or awareness during procedure. At discharge, three patients in group I and two patients in group II judged anesthesia as unpleasant, while remaining 27 patients in group I and 28 in group II found their experience of anesthesia pleasant.

BODY.DISCUSSION:
Propofol is widely used as an induction agent during general anesthesia. When combinations of intravenous anesthetic agents are given to patients, the effects or adverse effects result cannot be predicted from the knowledge of the dose requirements of individual agents.[34] Past studies have found that combinations of midazolam with thiopental, methohexital, propofol, alfentanil, and fentanyl are synergistic.[5] In contrast, ketamine has been found to be additive when combined with midazolam or thiopental using loss of response to verbal command as the end point. This study was conducted to compare ketamine with fentanyl as premedicant in propofol anesthesia with respect to hemodynamic and intraoperative or postoperative adverse effects.
Ketamine, a powerful analgesic, in subanaesthetic doses has recently gained more attention as an analgesic for total intravenous anaesthesia. It also possesses local anaesthetic properties with a direct inhibitory action on dorsal horn neurons of lamina I and lamina V. Pharmacological targets of ketamine are NMDA receptors, opioid receptors, muscarinic, and voltage sensitive Ca++ channel.[2]
In this study, the patients, in whom ketamine was administered, showed insignificant changes in hemodynamic. This may be attributed to the indirect action of ketamine that acts sympathetically on sinus node. In addition, ketamine premedication with propofol anesthesia attenuated the hemodynamic depression without causing any significant apnoea. After 10 min, it was observed that there was no significant change in hemodynamic parameters in the ketamine group. This may be due to cardiostimulant effect of ketamine that in subanesthetic doses may balance the cardiodepressant pressure effects of propofol. This was attributed to fentanyl that causes cardiovascular depression. The patients of group II in which fentanyl was administered, the mean systolic and diastolic pressure and pulse rate were reduced significantly at 1, 3, and 5 min.
The pain on propofol injection was similar in both the groups and the difference was statistically insignificant between two groups. The incidence of apnoea was significantly high in patients who received fentanyl as premedicant. Our results were comparable to other studies,[6–9] where fentanyl was used for propofol anesthesia. The awakening time, that is, the time taken when patient opened eyes on verbal commands, was longer in group I. Similarly, the recovery time, that is, when patient was able to answer simple questions such as name, age, date of birth, time, and place, was significantly higher in group I patients. In addition, there was no unpleasant emergence phenomenon reported in any of the patients of any group.
To conclude, ketamine, being a cardiostimulant drug, is better premedicant than fentanyl with respect to hemodynamic stability and adverse effects. The incidence of apnoea and respiratory depression is also less with ketamine, but the recovery was faster where fentanyl was administered.

Question: Compared to fentanyl injection (1.5 μg/kg) (group II) what was the result of ketamine injection 0.5 mg/kg  (group I) on incidence of apnoea?
Evidence:  incidence of apnoea was more in group II (P<0.05
Answer: significantly decreased