European Journal of Cardiovascular Medicine

Ondansetron, a 5HT3 serotonin receptor antagonist, has been used effectively for the prevention of post-spinal hypotension. The effect has been attributed to blocking BJR (Bezold-Jarisch Reflex) by the inhibitory effects of ondansetron on serotonin receptors. Frequent association of bradycardia and hypotension after induction of general anesthesia in patients warrants exploring the prophylactic effects of blocking serotonin receptors on preventing post-induction hypotension. Ketamine can be used to attenuate the hypotensive effect of an induction agent through indirect stimulation of the sympathetic nervous system with increased sympathetic outflow. This results in increased heart rate, systemic and pulmonary arterial pressure. However, only a limited number of studies have reported their efficacy in laparoscopic cholecystectomy. In the present study, we intend to compare the efficacy of ketamine and ondansetron, two of the commonly used drugs for the prevention of post-operative sour throat, nausea and vomiting [1,2,3,4] for their effect on the incidence of hypotension among patients undergoing laparoscopic cholecystectomy.

Aims And Objectives

In this study we wanted to determine the effect of low dose ketamine and ondansetron given before an induction agent on the prevention of hypotension, study the effect of the drugs on pre- and post-induction BP (Blood Pressure), study the effect of the drugs on other vitals and study the side effects, if any, associated with the drugs.

This double-blind, randomized controlled study was conducted among 56 patients coming for elective laparoscopic cholecystectomy at UPUMS Saifai, Etawah, from November 2018 to April 2020 after receiving approval from the institutional ethics committee (EC number: 156/2020-21 dated 21/06/2021) and the scientific committee of our tertiary care medical college. And  after taking written informed consent from the study participants. All procedures were conducted according to the Declaration of Helsinki over time.

Inclusion Criteria: This study included patients of either sex scheduled to undergo elective laparoscopic cholecystectomy, requiring general anesthesia, of ASA grades I and II, 18-60 years of age, and with BMI between 18-30 kg/m2.

Exclusion Criteria: Patients who refused to participate in the study, patient allergic to the study drug, patients of ASA III and above, patients with known hypertension, peripheral vascular disease, ischemic heart disease, cardiac arrhythmias, or having a cardiac pacemaker, patients taking any heart rate modifying drugs, MAOI (Monoamine Oxidase Inhibitors) or any drug affecting the autonomic nervous system and patients with preoperative bradycardia and tachycardia were excluded from the study.

Sample size calculation

The formula used for calculating the sample size in a comparative study of means (two-sample t-test):                                           

  n=(δ2⋅(Zα/2+Zβ)⋅σ

Where:

• n = sample size per group
• Za/2 = Z-value for the desired significance level (e.g., 1.96 for 95% confidence level)
• Zβ= Z-value for desired power (e.g., 0.84 for 80% power)
• σ \ sigma = assumed standard deviation of the variable being measured (in this case, 7)
• δ \ delta = absolute error (margin of error) around the mean (in this case, 3.64)
• Given the parameters provided:
• Significance level (α\alphaα) = 0.05 (corresponds to Z-value of 1.96)
• Power (1−β1 - \beta1−β) = 0.80 (corresponds to Z-value of 0.84)
• Standard deviation (σ\sigma) = 7
• Absolute error (δ\delta) = 3.64

Therefore, the calculated sample size per group is approximately 15.37. Rounding up to ensure adequate power and considering practicality in recruitment, a total sample size of 28 per group (as mentioned) was chosen, which is standard practice to ensure sufficient statistical power and reliability of findings.

Study Procedure: The study was conducted after approval from institutional ethical committee. 56 Patients were incluced in this study which were divided in two groups. In group A (n = 28) Ketamine 10 mg diluted upto 5 ml in normal saline.In group B( n = 28) Ondansetrone 4 mg diluted upto 5 ml in normal saline. All the patients were assessed before surgery and pre-anesthetic check-up was done including detailed history, general, systemic examination, and laboratory investigation. The proposed anesthetic technique was explained to the patients and written informed consent was taken.

Patients were randomly allocated into two study groups by using computer generated sealed study drug envelope technique.  In the operation theatre, Nil per orally (NPO) status were checked. 18G IV cannula was secured. Routine ASA monitors (NIBP, ECG, Pulse Oximeter and EtCo2) were attached to the patient and baseline vital values were recorded. IV fluid Ringer Lactate was started @ 10ml/kg body weight.

In the Group A, patients were given Inj. Ketamine 10mg diluted in 5ml normal saline just before induction. Similarly, in Group B, patients were given Inj. Ondansetron 4mg diluted in 5 ml normal saline just before induction.

Patients were premedicated with Inj. fentanyl (2 μg/kg) and Inj. Midazolam 1mg. After preoxygenation for 3 min before induction, induction was done with  Inj. Propofol (2 mg/kg) and relaxation with Inj. Vecuronium (0.1mg/kg) were given intravenously in both the groups. After complete relaxation, an appropriately sized endotracheal tube was inserted and connected to the ventilator circuit. Baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), Mean arterial pressure (MAP), heart rate (HR), SpO2, End tidal CO2 (EtCO2) were recorded. Then all the vitals were recorded just after giving the study drug, at the time of induction , immediately after intubation and every minute after intubation upto 10 minutes.  The anesthesiologist who administered the drugs and record vitals of the patients were blinded to the study. Hypotension was considered when there was a fall in MAP of at least 20% from baseline.

Post induction hypotension if not controlled by study drugs then it was first treated  by rapid infusion of 500 ml Ringer Lactate and if not controlled from this then rescue drug (Inj Mephentermine (3-6mg) IV stat) was given. Moreover, the cases with a decrease or increase in HR (20% change from baseline) were recorded.

Statistical Methods

The data was analyzed using SPSS (Statistical Package for Social Sciences) software, version 21.0. The chi-square test, independent samples ‘t’-test and paired ‘t’-test were used to compare the data. A ‘p’ value less than 0.05 indicated a statistically significant association. Data analysis is done for comparison of SBP, DBP and MAP at baseline and different follow up intervals between two study groups.

At baseline, mean (SBP) systolic blood pressure values were 125.11±7.57 mmHg and 122.36±8.58 mmHg, respectively, in groups A (ketamine) and B (ondansetron). Statistically, there was no significant difference between the two groups (p = 0.209).

Just after giving away the trial drug, mean systolic blood pressure was 135.82±12.14 mmHg in group A (ketamine) as compared to 122.82±11.16 mmHg in group B (ondansetron), thus showing a statistically significant difference between the two groups (p<0.001).

At induction, mean systolic blood pressure was 107.89±9.50 mmHg in group A (ketamine) as compared to 104.46±4.08 mmHg in group B (ondansetron). Statistically, there was no significant difference between the two groups (p = 0.085).

Immediately after intubation, mean systolic blood pressure was 132.86±14.78 mmHg in group A (ketamine) as compared to 125.75±10.78 mmHg in group B (ondansetron). Statistically, the difference between the two groups was significant (p = 0.045). Between 1 min post-intubation and 10 min post-intubation, mean systolic blood pressure values ranged from 124.18±8.54 mmHg (9 min) to 129.82±15.29 mmHg (3 min), respectively, in group A (ketamine) and from 120.36±7.87 mmHg (10 min) to 125.25±10.02 mmHg (1 min), respectively, in group B (ondansetron). At all the follow-up intervals, mean values were higher in group A (ketamine) as compared to group B (ondansetron), and the difference was also significant statistically at 3 min and 10 min post-intubation intervals (p<0.05). (Table : 1)

At baseline, mean diastolic blood pressure values were 80.86±6.53 mmHg and 77.82±6.09 mmHg, respectively, in groups A (ketamine) and B (ondansetron). Statistically, there was no significant difference between the two groups (p = 0.075).

Just after giving away the trial drug, mean diastolic blood pressure was 87.57±11.28 mmHg in group A (ketamine) as compared to 78.18±8.17 mmHg in group B (ondansetron), thus showing a significant difference between the two groups (p = 0.001).

At induction, mean diastolic blood pressure was 68.89±9.52 mmHg in group A as compared to 71.46±5.33 mmHg in group B (ondansetron). Statistically, there was no significant difference between the two groups (p = 0.222).

Immediately after intubation, mean diastolic blood pressure was 81.93±13.00 mmHg in group A (ketamine) as compared to 83.82±10.84 mmHg in group B (ondansetron). Statistically, the difference between the two groups was not significant (p = 0.556).

Between 1 min post-intubation and 10 min post-intubation, mean diastolic blood pressure values ranged from 78.14±7.95 mmHg (8 min) to 84.71±12.48 mmHg (3 min), respectively, in group A and from 77.00±5.99 mmHg (10 min) to 82.18±7.33 mmHg (2 min), respectively, in group B. Statistically, there was no significant difference between the two groups at any of the follow-up intervals. (Table : 2)

Just after giving away the trial drug, mean arterial blood pressure was 103.71±10.20 mmHg in group A as compared to 93.07±8.61 mmHg in group B, thus showing a significant difference between the two groups (p<0.001)

At induction, mean arterial blood pressure was 81.93±9.19 mmHg in group A as compared to 82.57±4.38 mmHg in group B. Statistically, there was no significant difference between the two groups (p = 0.740).

Immediately after intubation, mean arterial blood pressure was 98.86±12.67 mmHg in group A as compared to 96.36±6.45 mmHg in group B. Statistically, the difference between the two groups was not significant (p = 0.722).

Between 1 min post-intubation and 10 min post-intubation, mean arterial blood pressure values ranged from 93.29±8.38 mmHg (8 min) to 99.71±9.92 mmHg (3 min), respectively, in group A and from 91.21±6.11 mmHg (10 min) to 96.46±6.72 mmHg (2 min), respectively, in group B. Statistically, there was no significant difference between the two groups at any of the follow-up intervals. (Table : 3 and Graph :1).

Graph :1   Comparison of Mean arterial pressure (MAP) at baseline and different follow-up intervals between two study groups

Both groups were comparable in terms of demographic data and clinical characteristics. Statistically, no significant difference was observed in terms of age, gender, ASA physical status classification, and duration of surgery.

Approximately 10% of patients under general anesthesia experience clinically severe hypotension within 0–10 minutes of the anesthesia induction.[5] Laparoscopic cholecystectomy procedures require general anesthesia, individuals who undergo these procedures run the risk of experiencing hypotension from the induction of anesthesia. Nevertheless, in procedures performed under general anesthesia, a pressor response occurs after intubation. While spontaneous ventilation under general anesthesia has been considered a viable alternative strategy for short-stay operations in recent years,[6] intubation is still a mandatory tactic in actual practice to ensure patient safety, and thus carries a risk of pressor response. It's interesting to note that up to 10 minutes after intubation, the pressor response that causes a sharp rise in hemodynamic parameters continues.

Therefore, there is a short-term risk of anesthesia-induced hypotension and a short-term risk of intubation-induced pressor response associated with procedures like laparoscopic cholecystectomy that are performed under general anesthesia and require intubation. Laparoscopic cholecystectomy, however, is also associated with hemodynamic alterations linked to the creation of pneumoperitoneum and extubation, which may potentially carry a risk of hypotension.[5,6] Given these dynamic variations in hemodynamics, it's critical to plan ahead for the care of any hemodynamic event that can compromise the patient's cardiorespiratory stability.

In this study, we attempted to assess the efficaciousness of prophylactic administration of ondansetron or low-dose ketamine as a safeguard against hypotension linked to anesthetic induction. Numerous trials using regional anesthesia have demonstrated the preventive effects of both of these medications against anesthesia-induced hypotension.[5-8] Studies assessing its use in general anesthesia are scarce nonetheless.[9–11] As a result, no research has been done on its application to stop hypotension associated with induction anesthesia during a laparoscopic cholecystectomy. Thus, the current investigation was designed.

For ketamine, a fixed dose of 10 mg was diluted up to 5 ml in normal saline and for ondansetron a fixed dose of 4 mg was diluted up to 5 ml in normal saline. As far as dose selection was concerned, the focus was on using the optimum dose in order to ensure patient safety, as the patients were expected to experience a surge in hemodynamics as a result of intubation too. Studies involving regional anesthesia not requiring intubation have reported the use of 8 mg of ondansetron[12,13] and ketamine in weight dependent doses of 0.5 mg/kg (average dose for 50 kg weight = 25 mg)[14-16] to a fixed dose of 30 mg[17]. However, in the present study we used only the low dosages as for the reasons described above.

Studies involving the use of these drugs in general anesthesia have focused solely on low-dose combinations. Golparvar et al.[18] in a study among elderly patients undergoing procedures under general anesthesia reported the use of 4 mg of ondansetron as a preventive measure against hypotension, which is similar to the dose selected by us. Patel et al.[9] in a study involving laparoscopic cholecystectomy under general anesthesia used 0.3 mg/kg ketamine (average dose 15 mg/kg for 50 kg weight), while Ongewe et al.[10] and Parish et al.[11] used a 0.5 mg/kg ketamine dose (average 25 mg for 50 kg body weight). In our study, we chose a fixed dose of 10 mg ketamine, which is less than the average dose they used.

The reason for the selection of a low dose of ketamine was its rapid action [7]. Due to this rapid action, in order to avoid the interaction of the ketamine-induced protective effect against hypotension with that of pressor responses during intubation, we kept the dose of ketamine lower so that it might not interfere with or act in synergy with the pressor response. Thus, dose selection was a balancing act between the desired outcome and possible complications.

After reviewing the literature, we did not find any study comparing the two drugs at the dose combinations used by us. As a result, no study has compared the use of two drugs for general anesthesia procedures. In one study comparing the two drugs with dose combinations close to those used by us, Shakya and Chaturvedi (2010)[5] used 0.25 mg/kg ketamine (average dose 12.5 mg for 50 kg body weight) and ondansetron 4 mg in patients undergoing procedures under spinal anesthesia, hypotension was found to be significantly lower in the ketamine group (10%) as compared to that in the ondansetron group (22.5%). In fact, in their study, Inj ondansetron group had a higher hypotension rate as compared to the placebo group (20%). In another study comparing 0.25 mg/kg ketamine against a 4 mg fixed dose of ondansetron for control of hypotension among patients undergoing procedures under spinal anesthesia, Mohtadi et al.[6] also made similar observations as made by Shakya and Chaturvedi (2010) and found that the incidence of hypotension was 0%, 48.7% and 38.5%, respectively, in the ketamine, ondansetron and placebo (saline) groups. Wani and Katoch [8] also observed the same dose of ketamine (0.25 mg/kg) and ondansetron (4 mg) among patients undergoing spinal anesthesia.

In the current study, we were unable to detect a protective effect of ketamine at a slightly lower dose (10 mg fixed dose), but we did find that ondansetron had a slightly better position with no hypotensive events, compared to 3 (10.7%) hypotensive events in the ketamine group. This discrepancy could be due to differences in dose-selection as well as the type of anesthesia. Moreover, it must be kept in mind that pressor responses as a result of intubation could affect the performance of two drugs in a varied manner in cases of general anesthesia as compared to spinal anesthesia. There are only a few studies in the contemporary literature on patients undergoing general anesthesia. Moreover, there is no comparative study of two drugs for procedures conducted under general anesthesia or laparoscopic cholecystectomy.

Among studies showing the performance of the two trial drugs in general anesthesia, Golparvar et al., in a study among elderly patients undergoing procedures under general anesthesia, used ondansetron 4 mg and reported the incidence of hypotension to be 16% in ondansetron as compared to 45% in the placebo group, thus showing a protective effect of ondansetron. Hussein et al., in another study, reported the protective effect of ketamine, but at a much higher dose (30 mg). Onegwe et al., and Parish et al., in their studies, reported the protective effect of ketamine at a much higher dose (0.5 mg/kg, average 25 mg for 50 kg body weight). In the absence of a previous comparative study between two drugs for their protective effect against hypotension under general anesthesia, the results of the present study could only be attributed to a relatively much lower-dose of ketamine as well as a difference in the type of surgery.

The present study was limited by the absence of a placebo or control group and study is internally validated, which made it difficult to assess whether the use of either of the two drugs was actually instrumental in bringing about a phenomenal change in hypotensive events. After reviewing the literature, we did not come across any contemporary study that reported anesthesia induction induced hypotension to be a major issue among patients scheduled to undergo laparoscopic cholecystectomy under general anesthesia. The findings in the present study thus warrant further elaboration by using other drug-dose combinations, including the inclusion of a control group, and extending the observation period beyond the 10-minute post-intubation stage, as done in the present study. We recommend further studies with a larger sample size, taking these issues into consideration.

Post-induction anesthesia hypotension incidence was higher in ondansetron as compared to that in ketamine group; however, the difference was not significant statistically. It seemed that pressor responses following intubation superseded the hypotensive effect of inducing agent. Given the previous reports showing strong hemodynamic stress following intubation, the anesthesia induced hypotension does not seem to hold much relevance in context with laparoscopic cholecystectomy.

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