Cholecystectomy, the removal of the gallbladder, is a frequently performed surgical procedure on a global scale.[1] Two prevalent approaches to cholecystectomy are open cholecystectomy, a traditional surgical method involving a sizable incision, and laparoscopic cholecystectomy, a minimally invasive procedure utilizing small incisions and specialized instruments for gallbladder removal. [2] The evolution of laparoscopic techniques has been particularly notable in the management of cholelithiasis, with laparoscopic cholecystectomy emerging as a widely accepted alternative to traditional laparotomy for gallbladder removal.[3] The gold standard for cholecystectomy has shifted to a laparoscopic procedure with the introduction of laparoscopic surgery and laparoscopic cholecystectomy in the late 1980s.[4] Laparoscopic surgery has revolutionized surgical practices due to lower total medical expenses, decreased bleeding, fewer postoperative surgical and pulmonary problems, and quicker recovery times, since mid-1950s.[5] Traditionally, laparoscopic procedures are carried out when the patient is under general anaesthesia after insufflating carbon dioxide to create an artificial pneumoperitoneum that allows for a clear view of the abdominal contents.[6] Carbon dioxide (CO2) is the preferred gas due to its non-combustible nature, rapid clearance, and high solubility in blood. However, the drawback lies in CO2 absorption, which can lead to hypercapnia and respiratory acidosis.[7] During the creation of artificial pneumoperitoneum due to increased intra-abdominal pressure and the release of several neurohumeral components, various organ systems of the body experience major physiological changes like tachycardia and hypertension. These hemodynamic alterations also result in significant physiological changes. These changes are best managed by the use of general anaesthesia (GA).[8] Open cholecystectomy, in comparison to routine laparoscopic cholecystectomy, is associated with a higher incidence of complications.[9]

Complications such as bile leaks, bile duct injuries, and retained bile duct stones are frequently observed in open cholecystectomy. The economic implications of open cholecystectomy approach are substantial, with increased direct and indirect costs primarily attributed to extended hospital stays. Prolonged recovery times may result in extended periods away from work, further impacting individuals. The heightened complication rate may necessitate additional medical interventions and procedures, particularly in cases of bile duct injuries during the operation.[10]

Trendelenburg position is expected to confer respiratory advantages but may pose cardiovascular disadvantages.[11] Additionally, the anesthesia-induced hemodynamic response also has sequential effects.[12] The benefits of these positional changes must be carefully weighed against potential adverse effects associated with CO2 pneumoperitoneum. One notable concern is the potential for accelerated hypotension due to sympathetic blockade, as Regional Anesthesia may affect the normal autonomic regulation of blood pressure. Additionally, ventilatory changes can occur due to the higher sensory blockade and patients may experience shoulder-tip pain resulting from diaphragmatic irritation.[13,14] In routine practice, the conventional approach for securing the airway during laparoscopic surgery involves endotracheal intubation which is invariably associated with sympathetic stimulation which can lead to tachycardia, hypertension, and arrhythmias.[15] The hemodynamic changes induced by endotracheal intubation are typically transient, variable, and unpredictable. While these alterations may pose minimal risk to healthy individuals, they can be potentially hazardous in patients with history of pre-existing conditions such as hypertension, myocardial ischemia, cerebrovascular diseases, or elevated intraocular pressures.[16] Additionally, achieving effective ventilation is challenging due to the impact of artificial pneumoperitoneum and postural changes on airway pressure and pulmonary compliance.[17] However, the most common approach is general anesthesia with endotracheal intubation with controlled ventilation, offering airway protection and preventing aspiration pneumonia.[18,19]

This evolving understanding of the interactions between induction agents opens avenues for refining anesthetic protocols to achieve optimal sedation while minimizing adverse effects.[20,21]. This antagonism results in the blockade of spinal nociceptive reflexes and therefore, is widely used as a preventive analgesic for managing acute postoperative pain. This multifaceted role highlights the versatility of ketamine in anesthesia, establishing it as a valuable tool for optimizing patient comfort and recovery in the perioperative setting.[22,23] Despite its distinctive benefits, when used as a sole induction agent, ketamine has limitations due to its psychomimetic and sympathomimetic effects.[24] Utilization of Ketamine as an anesthetic is limited by several side effects such as nausea, vomiting, emergence hallucinations, and an increase in blood pressure and heart rate, attributed to its sympathomimetic effects and its potential to elevate intracranial pressure.[25]

Previous studies have provided evidence supporting the positive hemodynamic outcomes associated with 'ketofol,' and the safety and stability of this combination have been well-documented in various settings. [26,27] Additionally, the use of drug combinations, for example 'ketofol,' often results in a reduction of the total dose of each individual drug. This reduction can be advantageous in specific scenarios, such as managing patients in hemorrhagic shock, where minimizing the overall drug load may be a critical consideration for patient safety.[28]

The concept of combining ketamine with propofol, often referred as 'Ketofol,' has been suggested as a potential strategy to mitigate the hemodynamic adverse effects associated with each drug individually. This combination aims to achieve a stable hemodynamic profile during the induction of anesthesia, offering an additional advantage of reducing the incidence of postoperative nausea and vomiting (PONV) as well as postoperative shivering. [29,30]

Aim: to evaluate the difference in hemodynamics variable post-induction with propofol versus ketofol at different time interval in cholecystectomy.

This is a prospective, randomized, Interventional Comparative Study done in department of anaesthesis in general surgery operation theatre, DKS PGI hospital, Raipur, Chhattisgarh from January 2023 to January 2025 with permission from institutional ethics committee. Cases undergoing Elective Laparoscopic Cholecystectomy Surgeries under General Anaesthesia requiring endotracheal intubation. A sample of 36 cases in each group was calculated at 95% confidence and 80% power to predict the expected difference of 6.73(+-10.11) beats per minutes in both study groups at 1 min post induction as per seed article. This sample size was adequate to cover all other variables. Eligible study participants were randomly allocated into 2 study groups using computer generated random number table. The study was conducted in following two groups of patients. Each group was consisting of 36 patients-

• GROUP A - Patients received 1 mg/kg propofol plus 1 mg/kg ketamine (10 mg/ml dilution) diluted to 20 ml in a syringe as induction agent.
• GROUP B – Patients received 2 mg/kg propofol diluted to 20 ml with normal saline in a syringe as induction agent.

INCLUSION CRITERIA:

1. Patients willing to give written informed consent.
2. ASA Grade I & II Patients
3. Age Groups-18-55 years of either sex
4. Undergoing Laparoscopic Cholecystectomy              surgery under    GA          requiring endotracheal intubation.

EXCLUSION CRITERIA:

1. Patients with history of drug allergy, egg allergy.
2. Patients with uncontrolled hypertension and diabetes mellitus.
3. Patients with history of psychiatric illness.
4. Pregnant patients
5. Patients with BMI >30kg/m2

PRE ANAESTHETIC CHECKUP

All selected patients underwent pre anaesthetic checkup, which included:

1. History

• Any significant present/past medical/surgical history
• History of any previous surgery with significant anaesthetic complication.
• History of present or past medication and history of any drug allergy.

2. General physical Examination including vitals & airway assessment for difficult intubation.
3. Systemic examination included assessment of Respiratory, Cardiovascular, Central nervous system & spine, Gastrointestinal tract and other systems.
4. Investigations

• Hematological - Hb%, TLC, DLC, Platelet Count, BT, CT, PT, INR.
• Fasting / random blood sugar.
• Blood urea, Serum Creatinine.
• LFT, Serum electrolytes.
• Chest X-ray, ECG.
• Viral Markers

Informed and written consent was obtained after providing complete explanation regarding the study protocol and the procedure.

PROCEDURE

Patient identification, fasting status, written informed consent and PAC were checked. Intravenous access was taken. All Standard ASA multipara monitors (SPO2, ECG, NIBP) attached. Baseline Haemodynamic parameters such as HR, SBP, DBP, MAP, SPO2 were recorded.

Intravenous line was secured, and i.v. fluid Ringer Lactate was started at 10ml/kg/hour. Patients were premedicated with inj. ranitidine 50 mg i.v, inj. Metoclopramide 10mg i.v, inj. Glycopyrrolate 0.2 mg i.v. and inj. Midazolam 0.01mg/kg i.v. 5minutes prior to study drug. Haemodynamic variables (HR, SBP, DBP, MAP and SPO2) were recorded before induction (just prior to study drug)

Group-A: All patients received Inj Propofol 1mg/kg + Inj Ketamine 1mg/kg diluted to 20 ml in a syringe intravenously.

Group-B: All patients received Inj Propofol 2mg/kg diluted to 20 ml with normal saline in a syringe (10 mg/ml dilution) intravenously. Inj Rocuronium (0.9 mg/kg) was given as a muscle relaxant to facilitate endotracheal intubation. Haemodynamic variables (HR, SBP, DBP, MAP and SPO2) were recorded before intubation. Patient were ventilated with 100% oxygen for 90 seconds and under direct laryngoscopy trachea was intubated with appropriate size E.T.T. Bilateral air entry was checked & tube was fixed and Haemodynamic variables (HR, SBP, DBP, MAP, AND SPO2) were measured at 1,3,5,10 & 15 min after intubation until pneumoperitoneum is created. Then surgery was allowed to commence & anaesthesia was maintained with 60% Nitrous Oxide and 40% Oxygen, 0.6 - 0.8% sevoflurane & inj. Rocuronium 0.1mg/kg i.v sos. At the end of the surgery patient was reversed with Inj. Neostigmine (0.05mg/kg i.v.) and Inj. Glycopyrrolate (0.008mg/kg i.v.) & extubation was done, when patient fully awake and obeying verbal commands. Patient were shifted to recovery room. In recovery room patient were observed for any side effects.

OUTCOME VARIABLES

1. Mean Heart Rate,
2. Mean Systolic Blood Pressure,
3. Mean Diastolic Blood Pressure,
4. Mean of Mean Arterial Pressure,
5. Mean Rate Pressure Product
6. Mean SpO2,

Proportion of cases who will experience side effects.

STATISTICAL ANALYSIS

Data obtained in this study were processed in Microsoft Excel 2007. Qualitative data were measured as percentages and proportions while quantitative data was measured as mean and standard deviation from mean (SD). Appropriate statistical tests of significance were applied for analysis of the data collected using IBM SPSS Statistics version 22. The Categorical data was presented as numbers (percent) and were compared among groups using Chi square test. The quantitative data was presented as mean and standard deviation and were compared by students t-test. Probability was considered to be significant if less than 0.05.

The mean age of patients in Group A was 37.38±9.56years and in Group B was 36.94±8.08 years. Hence these groups were comparable with respect to age. Female patients are 16 and 14 respectively in both groups. Hence these groups were comparable with respect to sex. The mean Weight (kg.) of patients in Group A was 56.16±8.86 and in Group B was 55.41±9.36. Heart rate of patients in Group A was 85.1 ± 3.97 at baseline, 87.52 ± 2.93 just after induction of anaesthesia. The difference of Mean Heart Rate between these groups was statistically significant (P <0.05) at these time intervals. Group A exhibited significantly lower and stable heart rate as compared to Group B.

The difference of Mean Systolic Blood Pressure between these groups was statistically significant (P <0.05) at these time intervals except just after pneumoperitoneum created. Group B exhibited significantly lower Mean SBP as compared to Group A.

The difference of Mean Diastolic Blood Pressure between these groups was statistically significant (P <0.05) at these time intervals except just after pneumoperitoneum created. Group B exhibited significantly lower Mean DBP as compared to Group A.

The difference of Mean Arterial Blood Pressure between these groups was statistically significant (P <0.05) at these time intervals except just after pneumoperitoneum created it was not significant. Thus, in our study Group B showed significantly lower MAP as compared to Group A.

The difference of Mean Oxygen Saturation between these groups was statistically not significant (P >0.05) at these time intervals. Hence these groups were comparable with respect to Mean Oxygen Saturation at these time intervals.

The difference of Mean Rate Pressure Product between these groups was statistically significant (P <0.05) just after induction of anaesthesia, 1 min after Intubation (T1 ), 15 min after Intubation (T5) and just before pneumoperitoneum created. The difference of Mean Rate Pressure Product between these groups was statistically not significant (P >0.05) at all other time intervals. Hence these groups were comparable with respect to Mean RPP at these time intervals.

Group A exhibited less pain on injection.

Number of patients developed Shivering between the two study groups. In group A 28 patients experienced grade 0, 5 patients experienced grade 1, 2 patients experienced grade 2, 1 patient experienced grade 3 Shivering out of 36 patients and in group B 15 patients experienced grade 0 ,11 patients experienced grade 1, 5 patients experienced grade 2, 4 patient experienced grade 3 Shivering out of 36 patients. The difference of incidence of Shivering between the study groups was statistically significant (P <0.05). Significantly a greater number of patients suffered from shivering in group B as compared to group A.

The comparison of number of patients developed hypotension between the two study groups. In group A 2 patients had hypotension out of 36 patients and in group B 10 patients had hypotension out of 36 patients. The difference of incidence of hypotension between the study groups was statistically significant (P <0.05), showing more incidence of hypotension in group B as compared to group A.

The comparison of number of patients developed hypertension between the two study groups. In group A 5 patients had hypertension out of 36 patients and in group B 1 patient had hypertension out of 36 patients. The difference of incidence of hypertension between the study groups was statistically not significant.

The comparison of number of patients developed bradycardia between the two study groups. In group A 1 patient had bradycardia out of 36 patients and in group B 5 patients had bradycardia out of 36 patients. The difference of incidence of bradycardia between the study groups was statistically not significant.

The comparison of number of patients developed tachycardia between the two study groups. In group A 4 patients had tachycardia out of 36 patients and in group B 2 patient had tachycardia out of 36 patients. The difference of incidence of tachycardia between the study groups was statistically not significant.

The comparison of number of patients developed postoperative respiratory depression between the two study groups. In group A 2 patients had respiratory depression out of 36 patients and in group B 6 patients had respiratory depression out of 36 patients. The difference of incidence of respiratory depression between the study groups was statistically not significant.

The comparison of number of patients developed Hallucination \ Nystagmus \ Delirium in postoperative period between the two study groups.

In group A 4 patients had Hallucination \ Nystagmus \ Delirium out of 36 patients and in group B 1 patient had Hallucination \ Nystagmus \ Delirium out of 36 patients. The difference of incidence of Hallucination \ Nystagmus \ Delirium between the study groups was statistically not significant.

PONV Score between the two study groups at different times intervals in the postoperative period. The difference of PONV Score between the two study groups was statistically not significant at any time interval (p value >0.05).

Hemodynamic stability during surgery is one of the main goals of any anaesthesiologist. The anaesthesia associated transient hemodynamic instability may be seen during induction owing to specific characteristics of induction agent and also due to laryngoscopy and intubation associated symapathetic stimulation, surgical incision and during extubation. Propofol mixed with ketamine (ketofol) is popular for short procedural sedation and analgesia because it has the advantage of reduced adverse effects of each drug counteracting the undesirable effect of one drug with beneficial effect of another. There are a number of recent studies demonstrating the advantages of combination of ketamine and propofol, providing cardiovascular stability which could be comparable to etomidate, on the other hand, this combination does not lead to adverse effects of etomidate-associated adrenal insufficiency in critically ill or septic patients. However, there is scarcity of data which show comparable efficacy of combination of ketamine-propofol (ketofol) versus propofol as single drug as induction agents on haemodynamic stability during induction and intubation. This prompted us to undertake present study to evaluate effect of propofol and ketofol on haemodynamic response following induction and intubation during general anaesthesia. So, in our study, we aim to compare ketofol (ketamine + propofol) and propofol as an induction agents to achieve a stable hemodynamic profile during intubation and until creation of pneumoperitoneum in laparoscopic cholecystectomy.

We compared the hemodynamic variables between the two groups (HR, SBP, DBP, MAP) at various time intervals (baseline, just before induction of anaesthesia, immediately after intubation (T0) and then at 1 min, 3 min, 5 min, 10 min, 15 min after intubation and just before Pneumoperitoneum created.

The Mean baseline heart rate in Group A was 85.12 ± 3.97 bpm while in Group B was 85.48 ± 3.42 (p value 0.664). The Mean baseline systolic blood pressure in Group A was 127.69 ± 3.70 mmHg while in Group B was 127.68 ± 2.66 mmHg (p value 0.989). The Mean baseline diastolic blood pressure in Group A was 82.34 ± 3.60 mmHg while in Group B was 82.25 ± 4.53 mmHg (p value 0.925). The Mean arterial blood pressure in Group A was 97.45 ± 2.54 mmHg while in Group B was 97.39 ± 2.29 mm Hg (p value 0.916). The Mean oxygen saturation in Group A was 98.41 ± 1.42 while in Group B was 98.98 ± 1.45 (p value 0.929). The Mean rate pressure product in Group A was 10866.42 ±527.008 while in Group B was 10914.09 ± 454.81 (p value 0.682). Thus, both the groups were comparable with respect to mean baseline hemodynamic parameters.

HEART RATE

In our study we observed that in Group B, heart rate was significantly decreased in comparison to Group A just after induction, but after intubation heart rate increased and the difference between Group A (ketofol) & Group B (propofol) was significant. While in Group A heart rate showed a comparatively stable pattern from intubation to just before the creation of pneumoperitoneum. This shows stabilizing effect of ketofol on heart rate irrespective of stimulus like intubation and surgical incision.

These findings were similar to study done by Raman et. al[40] where the heart rate followed the stable trend after induction, during intubation, post-intubation after creation of pneumoperitoneum with ketofol. Similarly, Hamid Kayalha et. al[35] also found that heart rate was significantly lower in propofol group after induction, 5 min and 10 min after intubation when compared to ketofol group. In ketofol group, they found that heart rate followed a stable pattern after induction, 5 min and 10 min after intubation. The results of their study were consistent with our study. Aboeldahab H et. al[32] in a similar study also found ketofol more hemodynamically stable and their results were similar to our study. Seyoum Hailu et. al[39] also found the similar results where heart rate was significantly lower in the propofol group compared to ketofol group.

In our study we observed that after induction, systolic blood pressure was less in group B as compared to Group A. This difference was statistically significant, although the fall in the blood pressure in Group B could not be categorized under hypotension i.e it didn’t require any vasopressor support or fluid therapy. In Group A systolic blood pressure remained stable from induction to 10 min post intubation.

Our study was comparable with study conducted by Machhar et. al. [41] in which they also observed that ketofol group was better in respect of haemodynamic variations compared to propofol and etomidate alone. The findings were similar in another study done by Seyoum Hailu et. al [39] that the administration of ketofol for induction of general anesthesia provided stable systolic blood pressure than propofol during the first 30 min after induction. Similarly, Aboeldahab H et. al[32] also observed significantly lower systolic blood pressure in propofol group compared to ketofol post induction, post intubation at 5 min & 10 min. Similar results were observed by Ebru TK et. al[37] where ketofol group had comparatively more stable hemodynamics. Our findings have attributed that the presence of ketamine in the ketofol due to its sympathomimetic effects which counterbalances the hypotensive effect of propofol.

In our study we observed that Mean Diastolic Blood Pressure was significantly lower in group B than group A at post induction, T0, T1, T2, T3, T4. Although no significant hypotension occurred and blood pressure were within normal range. It shows that group A was better at maintaining diastolic blood pressure as compared to group B. Similar findings were also observed in study conducted by Aboeldahab et. al. [32] another study done by Manickam et. al[34] found the similar results. Raman et. al[40] also observed that ketofol group was better at maintaining hemodynamic stability in terms of heart rate, systolic blood pressure, Diastolic blood pressure and mean arterial pressure.

In our study we observed that the mean arterial pressure was significantly lower in group B than group A at various time intervals. Thus it shows that group A was better at maintaining hemodynamic stability as compared to group B. Our study is comparable with the study carried by Raman et al[40] which demonstrated that ketofol(1:1 mixture) produced better haemodynamic stability when compared to propofol group. Another study by Smischney NJ et al [36] also observed that combination of ketamine-propofol provide better hemodynamic stability during first 10 minutes after induction as compared to propofol used alone. Similarly, Aboeldahab H et al [32] where mean arterial pressure decreased in Group propofol after induction when compared to Group ketofol which is similar to our study. Similar results were found in a study conducted by Atashkhoyi S et. al[33] where mean arterial pressure decreased during induction in placebo group when compared to ketofol group. In a similar study Ramakrishna et. al[43] found there is decrease in mean arterial pressure in propofol group when compared with ketofol group which is similar to our study. The difference of Mean Oxygen Saturation between both the groups was statistically not significant (P >0.05) at various time intervals. Hence these groups were comparable with respect to Mean Oxygen Saturation at these time intervals.

Rate pressure product was stable throughout the study in group A while in group B there was a significant drop in rate pressure product after induction and intubation. After induction rate pressure product went upto 8031.336±380.34 in group B, the reason being hypotension and bradycardia associated with propofol. The findings are consistent with observations made by M Paulin et al[46] and Mangesh S Gore et al.[47] Rate pressure product is considered as surrogate marker of myocardial stress and oxygen consumption. The optimum range of RPP is said to be between 10,000 to 14,000 which gives minimal myocardial stress and myocardial oxygen demand. Both the drugs exhibit good safety profile in terms of levels of Rate pressure product. Levels of RPP>20,000 are more commonly associated with Myocardial ischemia and angina. So in both the groups in response to intubation, incision and creation of pneumoperitoneum, RPP didn’t critically rise, Hence it shows cardio stability of both the drugs.

In the postoperative period patients of both the study groups were monitored till 120 min (2 hours) at an interval 15 min for any postoperative side effects such shivering, hypotension, hypertension, bradycardia, tachycardia, respiratory depression, hallucination\ nystagmus\ delirium, nausea and vomiting. The results of our study showed that 8 patients had shivering in group A and 20 patients in group B had shivering in the postoperative period. The incidence of shivering was significantly less in group A than group B. Our results were consistent with study done by Cheong et al. [45] Findings have suggested that propofol inhibits thermoregulatory centres and decreases core body temperature which results in shivering. In contrary, study done by Raman et al[40] found no patients in either group had postoperative shivering.

In our study, 2 patients had hypotension in group A and 10 patients had hypotension in group B in the postoperative period which was statistically significant. Although group B showed increased incidence of hypotension but the reason may be related to fluid deficits, preexisting infection or post-surgical bleeding. Propofol related postoperative hypotension can be a matter of further research.

Incidence of hypertension was comparatively less in group B where only 1 patient had hypertension as compared to 5 patients in group A. Incidence of other side effects as bradycardia\tachycardia, respiratory depression, hallucination\nystagmus\delirium and postoperative nausea vomiting was also statistically insignificant.

Our results were concordant with the study done by Foo et. al. [37] they concluded that ketofol was more effective in reducing frequency of hypotension and there is no differences observed in terms of bradycardia, desaturation and respiratory depression in the postprocedural phase.

Our study concluded that induction of general anaesthesia in patients undergoing laparoscopic cholecystectomy with Ketofol is associated with a more stable haemodynamic stability without apparent side effects as compared to Propofol. Hence, the combination of ketamine and propofol proved to be significantly better than propofol alone.

LIMITATIONS

There were some limitations with our study:

• A small sample size limit the generalization of the findings to the broader population.
• We have not evaluated cost effectiveness of Ketofol compared to Propofol.
• In our study, we have focused on short term outcome, long term effects i.e cognitive dysfunction etc. might need to be considered in future studies.

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