Effects of Dexmedetomidine Infusion in Low Dose on Dose Reduction of Propofol, Intraoperative Hemodynamics, and Postoperative Analgesia in Patients Undergoing Laparoscopic Cholecystectomy.

Background: Dexmedetomidine, alpha 2 agonist, with its anxiolytic, sympatholytic and sedative property can be good adjuvant in anesthesia by modifying stress response to various stimuli during laparoscopic cholecystectomy including laryngoscopy, intubation, pneumoperitoneum, and extubation. We aimed to evaluate low dose dexmedetomidine for reducing hemodynamic perturbations to stressful events with secondary aim of evaluating propofol dose reduction and postoperative analgesia.
Methods: Sixty patients of American Society of Anesthesiologists Physical Status (ASA PS) Classes I and II were randomized to two groups of 30 each to receive dexmedetomidine infusion (0.5 mcg.kg-1.h-1) starting 15 min before induction (Group A) and normal saline (Group B). Patient induced and maintained with propofol infusion to keep BIS value 55-60 in both groups and heart rate (HR) and mean arterial pressure (MAP) were recorded. We stopped infusions at surgical closure. VAS score recorded till 24 h of surgery. Total propofol required in both groups were recorded. Data were statistically analyzed using the SPSS software version 15.0.
Results: MAP and HR remain elevated following intubation in Group B and remain so throughout procedure and during all stressful events including CO2 insufflation and tracheal extubation and were statistically significant. Significantly lower doses (almost 30%) of Propofol required in Group A to achieve similar BIS values compared to Group B. Visual Analog Scale score remained on the lower side in Group A for 24 h than Group B.
Conclusion: Low dose dexmedetomidine (0.5 mcg.kg-1.h-1) can effectively maintain hemodynamics during stressful events, reduces propofol requirement and improves postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Copyright:

INTRODUCTION

Laparoscopic cholecystectomy is a commonly performed minimally invasive procedure. It comes with multiple benefits over open procedure including lesser post-operative pain, reduced hospital stay and earlier functional recovery.[12] However it possesses greater challenge to anesthesiologist due to alteration in hemodynamics because of stress response generated by direct laryngoscopy, tracheal intubation, pneumoperitoneum, hypercapnea, patient positioning and extubation.[3] Hypercapnea can cause release of endogenous catecholamines leading to hemodynamic perturbations. Dexmedetomidine, a highly selective α2 adrenergic agonist, can reduce release of endogenous catecholamines and thereby reduce hemodynamic perturbations as well as anesthetic requirement and improve postoperative analgesia. So we aimed to compare the effect of low dose dexmedetomidine on anesthetic requirement, hemodynamics and postoperative analgesia.[456]

METHODS

This was aprospective randomized double blind placebo controlled trial, conducted during the period of July 2019 to December 2020 in a tertiary care institute after approval from institutional ethical committee and taking written informed consent from enrolled patients. The clinical research was done following the ethical principles for medical research involving human subjects in accordance with the Helsinki Declaration 2013. 60 patients of American Society of Anesthesiologists Physical Status (ASA PS) Classes I and II undergoing laparoscopic cholecystectomy and weighing 50–70 kg were equally randomized into two study groups using a predetermined computer generated random number allocation plan. Group A had 30 patients who received dexmedetomidine infusion (48 mL NS + 2 mL dexmedetomidine = 4 mcg.mL−1 of dexmedetomidine) at the rate of 0.5 mcg.kg−1.h−1 and 30 patients receiving normal saline infusion of 50 mL were categorized as Group B. Patients with history of diabetes, hypertension, severe cardiac disease, on β blockers or calcium channel blockers,α2 agonist, allergy to any of study drugs, egg proteins, pregnant and lactating mothers and refusal to give consent were excluded from the study.

Depending on the weight of the patient, the targeted infusion rate was set on pump and then it was covered with dark cloth so assessor was unaware of what drug patient was receiving. And this was decoded at the time of analysis only.

Once patient was on operation table, standard monitors were attached and baseline parameters including heart rate (HR), mean arterial pressure (MAP), systolic blood pressure, diastolic blood pressure and saturation (SPO2) were recorded. Two intravenous (i.v.) lines were secured one for infusing study drug and other for induction of anesthesia. Patients were premedicated with injection pantoprazole 40 mg i.v. and ondansetron 4 mg.

Patient was started with drug infusion for 15 min prior to induction. Patient was preoxygenated for 3 min and induced with injection propofol 2 mg.kg−1 and vecuronium 0.1 mg.kg−1 and patient's trachea was intubated with appropriate size endotracheal tube. Anesthesia was maintained with O2:N2O (50:50), and injection Vecuronium bromide as a muscle relaxantintermittently and Propofol infusion titrated to keep BIS value 55–60. Mechanical ventilation rate was adjusted to keep EtCO2 between 30 and 45 mm Hg. Surgeons were asked to keep intra abdominal pressure between 12 and 14 mm hg. Propofol infusion was stopped at the end of procedure. Reversal and extubation was done using neostigmine and glycopyrrolate and patient's trachea was extubated.

All the patients were observed for HR, MAP and SpO2 at regular intervals including baseline i.e., before starting infusion, 15 min after starting infusion, after induction, after intubation, after creation and deflation of pneumoperitoneum and after extubation and every 20 min intraoperatively. Time to first rescue analgesic requirement i.e., time from completion of injection of drug to the time postoperatively, when patient reported pain of ≥4 on visual analogue scale (VAS) was recorded. Injection diclofenac sodium 1.5 mg.kg−1 i.v. was used for rescue analgesia. Also mean propofol maintenance infusion rate and total amount of propofol required were calculated.

Sample size was calculated considering minimum mean difference of 25% in parameters with α = 0.01 and β = 0.20, sample size for each group was estimated as 28. 30 patients in each group were taken to round up figure. Data was presented in tables and statistically analyzed using The data was entered into Microsoft excel spread sheet and analysed by appropriate statistical software Statistical Package for the Social Sciences version 20.0 (SPSS Inc., Chicago, IL USA). Chi-square test was used for categorical data such as ASA PS classification and gender. Student's t-test was used for HR, blood pressure, oxygen saturation, end tidal carbon dioxide etc., for comparing within the group against baseline values. Intergroup differences in the data collected at each measured time point were determined using Student's t-test and intragroup differences from baseline within each group were determined by a paired t-test. P > 0.05 was considered insignificant, <0.05 as significant and highly significant if <0.001.

RESULTS

Both study groups were comparable with respect to age, gender, BMI, ASA status and procedural duration [Table 1]. So also baseline HR and the MAP were comparable.

Table 1

Demographic parameters

Parameters	Group A	Group B	P
Age	33.40±10.94	33.43±12.34	>0.05
Gender
Male	20	19	>0.05
Female	10	11
BMI (kg.m−2)	25.89±3.57	25.12±4.07	>0.05
ASA I	22	20	>0.05
ASA II	8	10
Duration of surgery (min)	39.27±4.56	40.97±2.88	>0.05

BMI=Body mass index, ASA=American Society of Anesthesiologists

Increase in HR as well as MAP were seen in group B after intubation which remain elevated throughout procedure and at various stressful events including skin incision, inflation of CO2 for pneumoperitoneum and extubation of patient's trachea [Tables 2 and 3]. Comparing these parameters amongst two groups showed statistically significant lower heart rate and MAP in Group A (dexmedetomidine group) as compared to Group B.

Table 2

Comparison of heart rate (beats/min) at various time intervals

Heart rate at various time intervals	Mean±SD		P
	Group A	Group B
Baseline	85.00±6.34	87.13±6.47	>0.05
After premedication (test drug preloading)	87.80±7.09	88.33±7.07	>0.05
After induction	84.93±6.34	85.67±6.50	>0.05
After intubation	85.60±6.09	97.00±6.47	<0.001
At skin incision	74.60±5.32	85.87±6.47	<0.001
After CO2 insufflation	73.13±5.30	85.60±5.93	<0.001
20 min after insufflations	73.20±5.19	85.47±6.47	<0.001
40 min after insufflations	74.47±8.44	85.73±6.94	<0.001
60 min after insufflation	73.73±6.97	85.67±9.68	<0.001
At exsufflation	74.23±6.90	86.33±7.50	<0.001
Just after reversal	73.57±8.44	86.67±8.19	<0.001
Just after extubation	74.53±7.80	86.80±7.36	<0.001

SD=Standard deviation

Table 3

Comparison of mean arterial blood pressure (mmHg) at various time intervals

Mean arterial blood pressure at various time intervals	Mean±SD		P
	Group A	Group B
Baseline	95.33±5.48	97.77±6.61	>0.05
After premedication (test drug preloading)	95.70±6.08	96.27±6.92	>0.05
After induction	94.90±5.46	97.67±6.54	>0.05
After intubation	87.21±5.96	96.73±6.59	<0.001
At skin incision	88.90±5.14	97.60±6.49	<0.001
After CO2 insufflation	88.67±5.11	97.60±6.26	<0.001
20 min after insufflations	88.70±5.60	97.57±7.14	<0.001
40 min after insufflations	91.42±5.07	97.95±6.35	<0.001
60 min after insufflation	81.40±5.84	94.79±6.25	<0.05
At exsufflation	84.02±4.15	95.12±6.38	<0.001
Just after reversal	83.62±4.92	94.73±6.22	<0.001
Just after extubation	81.97±4.51	95.79±6.11	<0.001

SD=Standard deviation

Similarly, BIS value in Group A was achieved by lower dose of propofol in Group A as compared to Group B and this difference was statistically significant as seen from Table 4. Required dose of Propofol for maintenance of anesthesia was almost 30% lesser in Group A than in group B.

Table 4

Comparison of propofol requirement between groups

Propofol requirement	Mean±SD		P
	Group A	Group B
Propofol dose (mg)	363.80±57.39	465.70±71.36	<0.001
Propofol per hour (mg.kg−1)	4.39±0.50	6.21±0.76	<0.001

SD=Standard deviation

In Group A, time for first rescue analgesia was earlier i.e., 66.0 min as compared to Group B which was 230 min. When VAS score was compared in both the groups, it was observed that patients in group Bhad higher VAS score than in Group A which was statistically significant [Table 5].

Table 5

Comparison of Visual Analog Scale score after extubation among study groups

VAS score	Mean±SD		P
	Group A	Group B
0 (min)	6.03±1.22	7.53±1.22	<0.001
30 (min)	5.53±1.14	6.60±1.22	<0.001
1 (h)	4.63±1.07	5.87±1.22	<0.001
6 (h)	3.87±0.97	5.10±0.92	<0.001
12 (h)	3.33±0.80	4.27±1.05	<0.001
24 (h)	2.39±0.18	3.67±1.09	<0.001

VAS=Visual Analog Scale, SD=Standard deviation

DISCUSSION

Laparoscopic surgeries with CO2 pneumoperitoneum are done with the intention of reducing trauma, morbidity, mortality, pain and stress response to surgery, hospital stay and health care costs. In laparoscopic surgery with pneumoperitoneum, hemodynamic perturbations can result in poor operative field, reduction in surgical success rate, increase in complications, resulting in increased postoperative hospital stay and health care cost. Various physiological methods and pharmacological agents have been tried for maintaining hemodynamics during laparoscopic surgery with varying degree of success.

Dexmedetomidine, a relatively new α2 agonist, provides dose dependent sedation, analgesia, sympatholysis, anxiolysis and controlled hypotension without relevant respiratory depression. Dexmedetomidine has also been found to be effective in attenuating pressor response to intubation and pneumoperitoneum. i.v. administration of dexmedetomidine in the perioperative period inhibits the release of endogenous catecholamines by activating vasomotor center in medulla and thereby reducing more than 50% of catecholamine level of body which helps to maintain hemodynamic stability intraopertaively.[46]

Sympathoadrenal response generated due to stressful events including laryngoscopy, endotracheal intubation, pneumoperitoneum and extubation can cause significant rise in heart rate and blood pressure. This was effectively attenuated in the group where dexmedetomidine was used as against the normal saline group in previous studies.[78910]

Propofol due to its safety and efficacy is commonly used as induction as well as maintenance agent. However, some recent literature has questioned the safety of even short term propofol infusion. This mandated a search for additive agent which can reduce the dose of Propofol required for induction as well as for maintenance.[1112]

With addition of dexmedetomidine before induction of anaesthesia, Bajwa et al.[13] found that there was a significant reduction in Propofol requirement during perioperative period. Similar effects were also observed by a study conducted by Kang et al.[14] and this was explained by the sedative property of dexmedetomidine, leading to faster onset of hypnosis. Our study also found noted a decrease in Propofol requirement during induction and maintenance and this decrease was around 30%.

Although laparoscopy is performed through miniature incisions, postoperative pain is still a matter of concern. As studied by Qin Ye et al.[15] and Chilkoti et al.,[16] dexmedetomidine could effectively relieve pain in postoperative period as well as improve recovery profile as it reduces postoperative inflammatory markers and substance P released by surgical trauma.[4]

Study by Park et al.[17] also showed that dose of dexmedetomidine, as low as 0.5 mcg.kg−1.h−1 is beneficial in reducing pain in postoperative period. In our study we used same infusion and found to have significant reduction in VAS score postoperatively.

CONCLUSION

The results of our study showed that dexmedetomidine infusion at the rate of 0.5 mcg.kg−1 not only attenuates stress response and maintains hemodynamic stability with decrease requirement of propofol but also provides good postoperative analgesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.