Laparoscopic cholecystectomy surgery is one of the most commonly undertaken procedure in general surgery with the overall complication rate being less than 1.5% and the mortality being less than 0.1% [1,2].The anaesthetist’s approach to anaesthesia for laparoscopic cholecystectomy surgeries has been giving attention on maintaining hemodynamic stability by avoiding hypotension, hypertension or tachycardia. The duration of pneumoperitoneum (PNP), likely carbon dioxide (CO2) insufflations, and patient positioning are also associated with hemodynamic instabilitycharacterized by decreased cardiac output, increased arterial pressures, increased systemic vascular resistance (SVR) and pulmonary vascular resistance(PVR) [3,4]. Various anaesthetic interventions like use combination of epidural and general anaesthesiaor epidural or segmental spinalcontrolled increase of intrathoracic blood volume (ITBV) by intravenous fluidsand pharmacological ways have been used by anaesthetist over the years to prevent or attenuate these unfavourable hemodynamic changes associated with pneumoperitoneum [5,6,7]. Clonidine a centrally acting selective partial α- 2 agonist is induce sedation, that hampers the release of catecholamine and vasopressin, thereby regulate the hemodynamic changes induced by pneumoperitoneum, increases cardiac baroreceptor reflex sensitivity to increase in systolic blood pressure and stabilizes blood pressure in patients undergoing laparoscopic cholecystectomy [8,9].Also, dexmedetomidine is another highly selective and potent specific α-2 agonist. It is seven to ten times more selective for α-2 receptors compared to clonidine and has lesser duration of action. Dexmedetomidine maintains blood pressure and heart rate and reduces the opioid requirements during pneumoperitoneum in laparoscopicsurgeries [10,11]. So, the present study was conducted withan aim to evaluate the efficacy of intravenous clonidine and dexmedetomidine in maintaining the perioperative hemodynamic parameters [systolic blood pressure (SBP),diastolic blood pressure (DBP),mean arterial pressure (MAP), heart rate (HR)] during pneumoperitoneum in laparoscopic cholecystectomy.

After approval from the institutional ethical committee, the present double blind randomized, prospective clinical study was carried out among patients (age: 20-50 years and ASA grade I and II) scheduled for elective laparoscopic cholecystectomy under general anaesthesia .

SAMPLE SIZE

The sample size was calculated as 90 using formula:n=4pq/d2 , where, n is sample size, p = 66% (prevalence of hemodynamic instability among patients during elective laparoscopic cholecystectomy), q=100-p and d is standard error = 10%. Patients with BMI>30, undergoing laparoscopic to open surgery conversion intraoperatively, allergy to the study drugs, cardiopulmonary and respiratory disorders, onantihypertensive drugs, with psychiatric illness, with renal and hepatic dysfunction, pregnant and lactating females were excluded from the study.

ANAESTHETIC METHODS

 A written informed consent was taken from patients who meet the inclusion criteria prior to intervention and a standardized protocol for anaesthesiawasfollowed for all cases.So, a total of 90 patients were enrolled in the study and were divided into 3 groups i.e. 30 patients in each group using computer generated randomization tables[Group A: 50 ml normal saline over a period of 10 minutes after induction and before pneumoperitoneum (PNP), followed by a continuous slow infusion at the rate of 0.5 ml/kg/hr; Group B: Clonidine 2µg/kg in 50ml normal saline over a period of 10 minutes after induction and before PNP, followed by a continuous infusion at the rate of 0.5 ml/kg/hr. (2 µg/kg/hr); and Group C: Dexmedetomidine 1µg/kg in 50mI normal saline over a period of 10 minutes after induction and before PNP, followed by a continuous infusion at the rate of 0.5 ml/kg/hr. (0.2 µg/kg/hr).

DATA COLLECTION

 Preanesthetic assessment of all the selected patients were done with complete history, general examination, airway assessment, systemic examination along with laboratory investigations (complete blood count, random blood sugar, kidney function test including serum electrolytes [Na+, K+], liver Function Test [AST, ALT, ALP], urine [Routine &Microscopic], chest Xray PA view and electrocardiogram). During perioperative period, hemodynamic parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were recorded various intervals [0 minute (Base value), D0 (Before study drug/immediate after intubation),D10 (After study drug), BPN (Beforepneumoperitoneum), APN for various intervals (after creation of pneumoperitoneum), RPN (Release of pneumoperitoneum), and AR (after reversal)]. Patients were closely observed for bradycardia or tachycardia (± 20% of basal value), hypotension/hypertension (± 20% of basal value), bradyarrhythmia and desaturation (<85%) during intra and postoperative period. During postoperative period along with above, nausea, vomiting,Respiratory depression, sedation and shivering were also recorded if occurred. Any complication if occurred was treated with appropriate medications.

STATISTICAL ANALYSIS Statistical analysis was performed by using chi square test/fisher exact test for categorical data. One way ANOVA test was used for comparing mean value between three groups. Paired t-test was used to test the relative change with respect to time. P-value less than 0.05 considered as significant at 95% confidence level. The statistical software IBM-SPSS version 25.0 was used in the analysis.

In present study the mean age (in years)for the groups A, B and C were 41.13±11.94, 40.70±13.85 and 39.20±14.26 respectively. The mean weight (in kg) for the groups A, B and C were 61.47±12.45, 58.03±9.99 and 63.93±12.50 respectively. In our study, majority of patients were females in group A, B and C. In present study the mean duration of surgery (in minutes) for the groups A, B and C were 72.43±6.48, 73.40± 6.01 and 73.80±6.01 respectively.In present study the mean duration of pneumoperitoneum (in minutes) for the groups A, B and C were 59.10±3.95, 60.03±3.46 and 60.23±3.65respectively. The baseline characteristics of the three were statistically comparable (p>0.05) (Table 1).

The mean HR (bpm) before induction in group A, B, and C was 87.30 ±12.31, 84.97±8.05 and 81.03±4.60 respectively.On comparing with the baseline values in group A, there was increase in HR to101.97±12.34 bpm immediately after intubation.Monitoring of mean HR to 15 minutes after reversal showed decrease in values to 89.77±7.13bpm. In group B, immediately after creation of PNP, HR increased to 95.47±10.33 bpm which came down towards theAPN10(86.47±7.80 bpm), APN30 (86.8±7.78 bpm), and APN90 (88.20±5.49 bpm). After infusion of loading dose of dexmedetomidine significant fall in mean HR was seen (±2.55 bpm) which remained similar to baseline values after creation of PNP (83.83±3.56 bpm). In group C, there was a slight increase in mean HR after reversal (94.73±9.18 bpm) which was similar to baseline value, after which HR decreased to 83.20±3.71 bpm, 15 min after reversal (Table 2).

Table 2: Comparison of heart rate during perioperative period among subjects in three groups

The mean SBP (mmHg) before induction in group A, B, and C was 126.0±10.92, 119.40±6.50, and 122.13±4.87 respectively. In group A, during whole PNP, no significant changes in SBP were observed as shown by values APN10 (122.13±4.87 mmHg), APN30 (122.57±7.05 mmHg), and APN50 (123.23±6.58 mmHg) (p>0.05). In group B, the release of PNP, SBP increased to 126.00±10.92, 119.40±6.50, and 122.13±4.87 mmHg followed by another rise in SBP after the reversal (119.97± 8.26) which decreased to 119.97±8.26 mmHg, 15 minutes after reversal. In group C, a significant fall in SBP was found after infusion of loading dose of dexmedetomidine (118.10±4.68 mmHg)which remained lower even after creation of PNP(124.67±9.89 mmHg) (Table 3).

Table 3: Comparison of systolic blood pressure during perioperative period among subjects in three groups

The mean DBP (mmHg) before induction in group A, B, and C was 81.40±9.43, 78.53±7.33, and 80.07±7.38respectively.In group A, during whole PNP, no significant changes in DBP were observed as shown by values APN10 (78.33±5.23 mmHg), APN30 (82.00±4.56 mmHg), andAPN50(82.90±3.61 mmHg). In group B, there was increase in DBP after the reversal (83.33±5.42 mmHg) which decreased to 78.13±5.12 mmHg, 15 minutes after reversal. In group C, after the release of PNP,DBP increased to 76.07±3.66 mmHg followed by rise in DBP after the reversal (76.90±5.51 mmHg) which decreased to 77.43±5.92mmHg,15 min after reversal (Table 4).

Table 4: Comparison of diastolic blood pressure during perioperative period among subjects in three groups

The mean MAP (mmHg) before induction in group A, B, and C was 91.57±5.49, 91.57±5.49, and 96.20±4.82 respectively. In group A, during whole PNP, insignificant changes in MAP were observed as shown by values APN10 (91.57±5.49 mmHg), APN30 (96.50±4.53mmHg), and APN50(97.67±4.68 mmHg). In group B, after the release of PNP, MAP increased to 96.20±4.82mmHg and remained significantly elevated after the reversal (101.67±4.69 mmHg) which gradually decreased to 94.17±6.01 mmHg 15 minutes after reversal. In group C, during the whole PNP, fall in MAP were observed as shown by values APN10(87.60±5.10 mmHg), APN30 (87.40±3.67 mmHg) and APN50 (86.90±3.47 mmHg) (Table 5).

Table 5: Comparison of meanarterial pressure during perioperative period among subjects in three groups

The sedation score in group A, B, and C was 1.37±0.61, 1.67±0.88 and 2.10±0.99 respectively and the difference in the three groups was statistically significant (p<0.05).

In present study, on comparing with the baseline values in control group, there was increase in HR to 101.97±12.34 bpm immediately after intubation. Monitoring of mean HR to 15 minutes after reversal showed decrease in values to 89.77±7.13bpm. In clonidine group, immediately after creation of PNP, HR increased to 95.47±10.33 bpm which came down towards the APN10(86.47±7.80 bpm), APN30 (86.8±7.78 bpm), and APN90 (88.20±5.49 bpm). After infusion of loading dose of dexmedetomidine significant fall in mean HR was seen (±2.55 bpm) which remained similar to baseline values after creation of PNP (83.83±3.56 bpm). In dexmedetomidine group, there was a slight increase in mean HR after reversal (94.73±9.18 bpm) which was similar to baseline value, after which HR decreased to 83.20±3.71 bpm, 15 min after reversal. Joris et al., observed the similar results with the use of clonidine as a premedication in a dose of 8µg/kg [8].Kalra et al., used clonidine 1µg/kg iv over a period of 15 minutes before pneumoperitoneum and observed significantly better hemodynamic control than control group [12].Roy et al compared intravenous clonidine (2.25µg/kg bolus and 0.9µg/kg/hr. infusion) and IV lignocaine (1.5µg/kg bolus and 0.6µg/kg/hr. infusion) in laparoscopic hysterectomy and attenuation in heart rate was significantly more in clonidine group [13]. Hazra et al., observed the similar results with administered of IV clonidine 1µg/kg, IV dexmedetomidine 1µg/kg and normal saline in three different groups, 15 minutes prior to induction. There was significant reduction in mean heart rate at various intervals during pneumoperitoneum. These findings are very similar to our study which stated that dexmedetomidine provides better heart rate control as compared to clonidine and control group in laparoscopic surgeries [14]. Bhattacharjee et al., observed the similar results with the use of dexmedetomidine at an infusion rate of 0.2µg/kg/hr. and observed that heart rate decreased significantly after intubation and pneumoperitoneum and remained lower throughout the pneumoperitoneum in comparison to control group (p0.05) in DBP were observed at all intervals except at 30 minutes after pneumoperitoneum (APN30) and after reversal(DBP_AR).While comparing Dexmedetomidine group with clonidine group, insignificant fall (p>0.05) in SBP and MAP were observed at all intervals except at 50 minutes after pneumoperitoneum (APN50). Hazraet al., compared clonidine 1 µg/kg iv and dexmedetomidine 1µg/kg iv and observed no significant difference in SBP,DBP and MAP in both groups while controlling stress response during pneumoperitoneum, whereas both drugs were effective in attenuating hemodynamic changes of pneumoperitoneum. Our finding was similar to these observations [13]. Joris et al., observed that pneumoperitoneum results in an increase in MAP, SVR, PVR and decrease in cardiac output. The increase in SVR was associated with marked release of vasopressin and catecholamines.Clonidine (8µg/kg) given before pneumoperitoneum reduced the release of catecholamine’s and thus significantly attenuated the increase in MAP and heart rate in comparison to placebo [16]. Passiet al., observed that with oral clonidine(150µg) premedication 60-90 minutes before laparoscopy, change in MAP was significantly lower and MAP varied between 88±9 to 95±9 mmHg as compared to control group (vit B complex tablets) in which MAP varied between 97±14 to106±5 mmHg [17]. Studies by Gupta et al., Bhandari et al., Yu et al., Sung et al., and Chandrashekariah et al., also observed similar findings [18,19,20,21,22]. In present study mean sedation score after extubation was measured using Ramsay sedation score. The sedation score in group A, B, and C was 1.37±0.61, 1.67±0.88 and 2.10±0.99 respectively and the difference in the three groups was statistically significant (p<0.05). .Similar results were found in study done by Kumar et al., they found that dexmedetomidine provided longer duration of analgesia and significantly higher sedation than clonidine [23].

Creation of pneumoperitoneum in laparoscopic abdominal surgeries produces significant increase of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP).During pneumoperitoneum in laparoscopic abdominal surgeries both intravenous clonidine and intravenous dexmedetomidine results to attenuate in all hemodynamic parameters (HR, SBP, DBP and MAP)During pneumoperitoneum in laparoscopic surgeries heart rate is better controlled bydexmedetomidine. However, dexmedetomidine and clonidine are equally effective for controlling blood pressure.Both the drugs have no respiratory complications seen but dexmedetomidine produces higher sedation as compared to clonidine.No complications were observed with both study drugs.

1. Soper NJ, Stockmann PT, Dunnegan DL, Ashley SW. Laparoscopic cholecystectomy. The new 'gold standard'? Arch Surg. 1992;127(8):917-21
2. NIH Consensus conference. Gall stones and laparoscopic cholecystectomy.JAMA. 1993;269(8):1018-24.
3. Ivankovich AD, Miletich DJ, Albrecht RF, Heyman HJ, Bonnet RF. Cardiovascular effects of intraperitoneal insufflation with carbon dioxide and nitrous oxide in the dog. Anesthesiology. 1975;42(3):281-7.
4. Struthers AD, Cuschieri A. Cardiovascular consequences of laparoscopic surgery. Lancet. 1998;352(9127):568-70.
5. Youssef MA, saleh Al-Mulhim A. Effects of different anesthetic techniques on antidiuretic hormone secretion during laparoscopic cholecystectomy. Surg Endosc. 2007;21(9):1543-8.
6. van Zundert AA, Stultiens G, Jakimowicz JJ, Peek D, van der Ham WG, Korsten HH, et al. Laparoscopic cholecystectomy under segmental thoracic spinal anaesthesia: a feasibility study. Br J Anaesth. 2007;98(5):682-6.
7. Junghans T, Modersohn D, Dörner F, Neudecker J, Haase O, Schwenk W. Systematic evaluation of different approaches for minimizing hemodynamic changes during pneumoperitoneum. Surg Endosc. 2006;20(5):763-9. 8. Joris JL, Chiche JD, Canivet JL, Jacquet NJ, Legros JJ, Lamy ML. Hemodynamic changes induced by laparoscopy and their endocrine correlates: effects of clonidine. J Am Coll Cardiol. 1998;32(5):1389-96.
8. Harron DW, Riddell JG, Shanks RG. Effects of azepexole and clonidine on baroreceptor mediated reflex bradycardia and physiological tremor in man. Br J Clin Pharmacol. 1985;20(5):431-6.
9. Hunter JC, Fontana DJ, Hedley LR, Jasper JR, Lewis R, Link RE, et al. Assessment of the role of alpha2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br J Pharmacol. 1997;122(7):1339-44.
10. Guler G, Akin A, Tosun Z, Eskitascoglu E, Mizrak A, Boyaci A. Single-dose dexmedetomidine attenuates airway and circulatory reflexes during extubation. Acta Anaesthesiol Scand. 2005;49(8):1088-91.
11. Kalra NK, Verma A, Agarwal A, Pandey H. Comparative study of intravenously administered clonidine and magnesium sulfate on hemodynamic responses during laparoscopic cholecystectomy. J Anaesthesiol Clin Pharmacol. 2011;27(3):344-8.
12. Roy S, Chaudhuri A, Saha D, Maulik SG, Bandopadhyay AK. Comparative study of clonidine versus lidocainefor attenuation of hemodynamic responses during laparoscopic hysterectomy. J Basic Clin Reprod Sci. 2014;3(1):38–43.
13. Hazra R, Manjunatha SM, Manuar MDB, Basu R, Chakraborty S. Comparison of the effects of intravenously administered dexmedetomidine with clonidine on haemodynamic responses during laparoscopic cholecystectomy Anaesth Pain Intens Care. 2014;18(1):25- 30.
14. Bhattacharjee DP, Nayek SK, Dawn S, Bandopadhyay G, Gupta K. Effects of dexmeditomidine on haemodynamics in patients undergoing laparoscopic cholecystectomy – A comparative study. J Anaesth Clin Pharmacol. 2010;2(1):45–8.
15. Koivusalo AM, Scheinin M, Tikkanen I, Yli-Suomu T, Ristkari S, Laakso J, et al. Effects of esmolol on haemodynamic response to CO2 pneumoperitoneum for laparoscopic surgery. Acta Anaesthesiol Scand. 1998;42(5):510-7.
16. Passi Y, Raval B, Rupakar VB, Chadha IA. Effect of oral clonidine premedication on hemodynamic response during laparoscopic cholecystectomy. J Anesth Clin Pharmacol. 2009;25(3):329–32.
17. Gupta K, Lakhanpal M, Gupta PK, Krishan A, Rastogi B, Tiwari V. Premedication with clonidine versus fentanyl for intraoperative hemodynamic stability and recovery outcome during laparoscopic cholecystectomy under general anesthesia. Anesth Essays Res. 2013;7(1):29-33.
18. Bhandari D, Tidke S, Sharma V, Dongre H, Garg D, Dhande P. Hemodynamic changes associated with laparoscopic cholecystectomy: effect of oral clonidine premedication. JPharmacy.2012;2(4):72-7.
19. Yu HP, Hseu SS, Yien HW, Teng YH, Chan KH. Oral clonidine premedication preserves heart rate variability for patients undergoing larparoscopic cholecystectomy. Acta Anaesthesiol Scand. 2003;47(2):185-90.
20. Sung CS, Lin SH, Chan KH, Chang WK, Chow LH, Lee TY. Effect of oral clonidine premedication on perioperative hemodynamic response and postoperative analgesic requirement for patients undergoing laparoscopic cholecystectomy. Acta Anaesthesiol Sin. 2000;38(1):23-9.
21. Chandrashekaraiah MM, Upadya DM, Jayachandran SP, Wali M. Effects of clonidine premedication on hemodynamic changes during laparoscopic cholecystectomy-A randomized control study. Applied Cardiopulmonary Pathophysiology.2011;15:91-8.
22. Kumar S, Kushwaha BB, Prakash R, Jafa S, Malik A, Wahal R et al. Comparative study of effects of dexmeditomidine and clonidine premedication in perioperative haemodynamic stability and postoperative analgesia in laparoscopic cholecystectomy. Internet JAnaesthesiol.2014;33(1):1-14.