A comparative study of esmolol and dexmedetomidine on hemodynamic responses to carbon dioxide pneumoperitoneum during laparoscopic surgery.

BACKGROUND: Carbon dioxide pneumoperitoneum for laparoscopic surgery increases arterial pressures, heart rate (HR), and systemic vascular resistance. In this randomized, single-blind, placebo-controlled clinical study, we investigated and compared the efficacy of esmolol and dexmedetomidine to provide perioperative hemodynamic stability in patients undergoing laparoscopic cholecystectomy.
METHODS: Sixty patients, of either sex undergoing elective laparoscopic cholecystectomy, were randomly allocated into three groups containing twenty patients each. Group E received bolus dose of 500 μg/kg intravenous (IV) esmolol before pneumoperitoneum followed by an infusion of 100 μg/kg/min. Group D received bolus dose of 1 μg/kg IV dexmedetomidine before pneumoperitoneum followed by infusion of 0.2 μg/kg/h. Group S (control) received saline 0.9%.
RESULTS: Mean arterial pressure and HR in Group E and D were significantly less throughout the period of pneumoperitoneum in comparison to Group S. IV nitroglycerine was required in 45% (9 out of 20) patients in Group S to control intraoperative hypertension, and it was clinically significant in comparison to Group E and D.
CONCLUSION: Both esmolol and dexmedetomidine attenuate the adverse hemodynamic response to pneumoperitoneum and provide hemodynamic stability during laparoscopic surgery.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Carbon dioxide (CO2) is commonly used to create pneumoperitoneum for laparoscopic surgical procedures.[12] Both CO2 and pneumoperitoneum cause adverse cardiovascular effects.[3] Adverse cardiovascular changes are characterized by elevation of arterial pressure and systemic vascular resistance and decreased cardiac output.[4] These hemodynamic responses are mainly due to increased release of catecholamines, vasopressin, or both.[56] Attenuation of adverse hemodynamic response to pneumoperitoneum is usually done by opioids,[7] vasodilators,[8] and α2 adrenergic agonists.[910]

Esmolol, an ultrashort-acting cardioselective β1 adrenoceptor antagonist, has been used to control tachycardia and hypertension. Esmolol blunts adrenergic responses to perioperative noxious stimuli effectively.[11] Koivusalo et al.[12] have shown that esmolol is effective in attenuating the adverse hemodynamic response to CO2 pneumoperitoneum.[12]

Dexmedetomidine, an α2 adrenergic receptor agonist, possesses hypnotic, sedative, anxiolytic, sympatholytic, and analgesic properties without producing significant respiratory depression.[13] Its sympatholytic effect decreases mean arterial pressure (MAP) and heart rate (HR) by reducing norepinephrine release.[14] Bhattacharjee et al.[10] have shown that dexmedetomidine is effective in attenuating the adverse hemodynamic response to CO2 pneumoperitoneum.[10]

In this study, the researchers wanted to compare the efficacy of esmolol and dexmedetomidine administered before pneumoperitoneum to attenuate the adverse hemodynamic response to laparoscopic surgery.

METHODS

The study protocol was approved by the Institutional Ethics Committee, and informed consent was obtained from the individual patients. Sixty American Society of Anesthesiologists’ (ASA) Grade I and II patients, aged 20–60 years, undergoing elective laparoscopic cholecystectomy under general anesthesia were randomly assigned to one of the three groups of 20 patients each: Group E (esmolol group), Group D (dexmedetomidine group), and Group S (control group). Power calculations suggested that a minimum of 17 subjects per group were required to detect 10% difference in arterial pressure between groups (a = 0.05, b = 0.80) to accommodate the probable dropouts, a number of twenty patients in each group were included in the study. Patients in whom surgery could not be completed laparoscopically and open cholecystectomy done were excluded from the study.

Patients with preexisting hypertension, bronchial asthma, diabetes, sinus bradycardia, and severe hepatic, renal, endocrine and cardiac dysfunction were excluded from the study. Patients were then randomly allocated (using computer-derived random number sequence) into three groups (n = 20) to receive one of the following regimens: Group E received bolus dose of 500 µg/kg intravenous (IV) esmolol before pneumoperitoneum followed by an infusion of 100 µg/kg/min. Group D received bolus dose of 1 µg/kg IV dexmedetomidine before pneumoperitoneum followed by infusion of 0.2 µg/kg/h. Group S received saline 0.9%.

All the patients were given diazepam 10 mg and ranitidine 150 mg orally on the night before surgery and tablet ranitidine was repeated on the morning of surgery. On arrival to operation theater, routine ASA monitoring (electrocardiography, pulse oximetry, and noninvasive blood pressure) was started and baseline vital parameters, for example, HR, MAP, and arterial oxygen saturation were recorded. An IV line was started. Patients were induced with fentanyl 2 µg/kg and propofol 2 mg/kg intravenously (IV). Endotracheal intubation was facilitated by muscle relaxant rocuronium 0.7 mg/kg. Anesthesia was maintained with 33% O2 in N2O, 0.6% isoflurane, and intermittent bolus dose of rocuronium. Patients received additional doses of fentanyl 1 µg/kg (IV) at half hourly intervals. Group E patients received bolus dose of 500 µg/kg IV esmolol before pneumoperitoneum followed by an infusion of 100 µg/kg/min. Group D received bolus dose of 1 µg/kgIV dexmedetomidine before pneumoperitoneum followed by infusion of 0.2 µg/kg/h and those allocated in Group S received 0.9% saline. CO2 was insufflated into the peritoneal cavity to create pneumoperitoneum. Intra-abdominal pressure (IAP) was maintained up to 12 mmHg throughout the laparoscopic procedure. All the patients were positioned in a head-up tilt of 15°. The patients were mechanically ventilated to keep end-tidal CO2 between 35 and 45 mmHg. Injection paracetamol 1000 mg was infused IV in every patient.

In cases of acute and severe hemodynamic fluctuations, the following medical interventions were taken:

Bradycardia (HR <60 beats/min), bolus dose of 0.6 mg atropine IV;

Hypotension (MAP <60 mmHg), increased rate of infusion of IV fluid, and/or bolus dose of phenylephrine 100 mcg IV and;

Hypertension (MAP >110 mmHg) nitroglycerine infusion IV.

At the end of the surgery, ondansetron 4 mg was administered IV for prophylaxis against nausea and vomiting. Residual neuromuscular block was reversed with appropriate doses of neostigmine and glycopyrrolate, and tracheal extubation was performed. HR and MAP were recorded at the following points of time:

Baseline

3 min after endotracheal intubation

Before pneumoperitoneum

10 min after pneumoperitoneum

20 min after pneumoperitoneum

30 min after pneumoperitoneum

40 min after pneumoperitoneum

50 min after pneumoperitoneum

After release of pneumoperitoneum

After extubation.

Patients were observed for adverse events, for example, bradycardia, hypotension, and hypertension during postoperative period in postanesthesia care unit.

Statistical analysis

The numerical data obtained from the study were expressed as mean ± standard deviation comparison between groups were performed with Kruskal–Wallis one-way analysis of variance by ranks or Fisher's exact test for small samples with a 5% risk. Mann–Whitney–Wilcoxon tests were performed when normality tests failed (GraphPad InStat, version 3.05, GraphPad Software, San Diego, CA, USA).

RESULTS

The patients allocated into the Group E, Group D, and Group S was comparable with respect to age, distribution of gender, body weight, and the duration of surgery [Table 1]. No significant difference was found regarding the preoperative MAP and the MAP values following intubation and before pneumoperitoneum among all three groups (P > 0.05) [Table 2]. However, following pneumoperitoneum, MAP values in Group E and Group D were significantly lower compared to Group S at 10, 20, 30, 40, and 50 min after pneumoperitoneum, following the release of CO2 and after extubation (P < 0.05) [Table 2]. On comparing patients in Group E and Group D, no significant difference in MAP was found at any time interval.

Table 1

Patient's characteristics and duration of surgery (mean±SD)

Table 2

Changes in mean arterial pressure

Similarly, no significant difference was found between the preoperative HR, and the HR values following intubation and before pneumoperitoneum among all three groups (P > 0.05) [Table 2]. However, following pneumoperitoneum, HR values in Group E and Group D were significantly lower compared to Group S at 10, 20, 30, 40, and 50 min after pneumoperitoneum, following the release of CO2 and after extubation (P < 0.05) [Table 3]. On comparing patients in Group E and Group D, no significant difference in HR was found at any time interval.

Table 3

Changes in heart rate (mean±SD)

Three patients of Group E and two patients of Group D suffered from bradycardia in our study, but the incidences are not statistically significant [Table 4]. Hypertension occurred in nine patients (45%) of Group S, whereas no patients of Group E and D suffered from hypertension. There was no incidence of hypotension in any group [Table 4].

Table 4

Distribution of patients according to adverse effects. Values are in number

When the groups were compared for the parameters of recovery-extubation time, response to verbal commands, and time for orientation, there were no significant differences among the groups (P > 0.05) [Table 5].

Table 5

Recovery time (minutes) (mean±SD)

DISCUSSION

In the study, we observed and compared the effects of esmolol and dexmedetomidine, administered before pneumoperitoneum, on hemodynamics in patients undergoing laparoscopic cholecystectomy.

In laparoscopic surgery, CO2 is routinely used to create pneumoperitoneum.[12] Immediately after pneumoperitoneum, plasma levels of catecholamines and vasopressin are increased. Increased catecholamine level activates the renin-angiotensin-aldosterone-system leading to some of the characteristic hemodynamic alterations such as elevated arterial pressure and increased systemic/pulmonary vascular resistance.[45] Vasopressin also contributes to elevation of arterial pressure by increasing the systemic vascular resistance.[6] Drugs such as α2 adrenergic agonists[910] and magnesium sulfate[15] have been successfully used for attenuating the rise in MAP and HR in response to pneumoperitoneum during laparoscopic surgery.

Esmolol is an ultrashort-acting cardioselective β1 adrenoceptor antagonist and is found effective to attenuate adrenergic responses to perioperative noxious stimuli.[1116] Esmolol has been successfully used for tracheal intubation,[17] maintenance of anesthesia,[16] and emergence from anesthesia and extubation.[11] It has been also used to blunt pressor and HR response to noxious stimuli. The hemodynamic effects of esmolol are thought to be mediated by blockade of peripheral beta-adrenergic receptors. Koivusalo et al.[12] have used esmolol in an initial bolus of 1 mg/kg before pneumoperitoneum and followed by an infusion of 200 µg/kg/min. They observed that esmolol was effective in attenuating the rise of HR and arterial pressure during laparoscopic surgery.[12] In our institution, we tried the similar doses of esmolol (both bolus and infusion), but we found that incidence of bradycardia was too high to be acceptable. The recommended bolus dose of esmolol varies between 250 µg/kg and 1 mg/kg and infusion ranges from 50 to 300 µg/kg/min. Hence, in our study, we used bolus dose of 500 µg/kg IV esmolol before pneumoperitoneum followed by an infusion of 100 µg/kg/min and still found that the dose was effective.

Dexmedetomidine is an α2 adrenergic receptor agonist having hypnotic, sedative, anxiolytic, sympatholytic, and analgesic properties without producing significant respiratory depression.[13] Activation of receptors in the brain and spinal cord level inhibits neuronal firing, thereby causing hypotension, bradycardia, sedation, and analgesia.[18] Presynaptic activation of α2 adrenergic receptors inhibits the release of norepinephrine. Postsynaptic activation of α2 adrenergic receptors inhibits sympathetic outflow and therefore decrease blood pressure and HR.[19] Dexmedetomidine does not appear to have any direct effect on heart.[20] Bhattacharjee et al.[10] have used dexmedetomidine in a bolus dose of 1 µg/kg IV before pneumoperitoneum followed by infusion of 0.2 µg/kg/h; they found that dexmedetomidine is effective in attenuating the adverse hemodynamic response to CO2 pneumoperitoneum.[10] In our study, we administered that dose of dexmedetomidine to the patients of Group D.

In our study, baseline MAP and MAP after intubation and before pneumoperitoneum was comparable between the three groups. However, MAP was significantly lower throughout the period of CO2 pneumoperitoneum and after extubation in patients of Group E and Group D compared to patients of Group S. We observed the similar finding in the case of HR also. Hence, both esmolol and dexmedetomidine administered intravenously before and during pneumoperitoneum were effective in attenuating the increase in MAP and HR during CO2 pneumoperitoneum.

Diamant et al.[21] reported 35% decrease in cardiac output in dogs with a raised IAP of 40 mmHg. Ishizaki et al.[22] tried to evaluate the safe IAP during laparoscopic surgery. They observed significant fall in cardiac output at 16 mmHg of IAP and hemodynamic alterations were much less at 12 mmHg of IAP. Hence, in our study, we kept IAP 12 mmHg. In spite of maintaining normocapnia and keeping IAP 12 mmHg, there was a significant rise of MAP and HR in patients of Group S during pneumoperitoneum. However, in Group E and D, hemodynamic responses to pneumoperitoneum were effectively blunted, and both the MAP and HR were remained at a significantly lower level compared to Group S. Recovery times are comparable in all the groups.

As far as the adverse effects are concerned, no patient of either group suffered from hypotension and bradycardia in our study. Hypertension occurred in nine patients (45%) of Group S for which they had to be treated with nitroglycerin infusion, whereas no patient of Group E and D suffered from hypertension.

CONCLUSION

Both esmolol and dexmedetomidine effectively attenuates the elevation of MAP and HR during and after pneumoperitoneum and thereby provides hemodynamic stability during laparoscopic surgery. There is no significant difference between the efficacy of esmolol and dexmedetomidine regarding the attenuation of hemodynamic response to pneumoperitoneum to laparoscopic surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.