Comparative Evaluation of Dexmedetomidine and Pregabalin as Premedication Agent to Attenuate Adverse Hemodynamic and Stress Response in Patients Undergoing Laparoscopic Cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy is the most commonly performed laparoscopic procedure. The goal of anesthetic management is to minimize stress response and early discharge. Dexmedetomidine, and pregabalin have been used successfully to attenuate laryngoscopy and intubation response in various surgical procedures. AIM: To compare efficacy of pregablin and dexmedetomidine in attenuating hemodynamic and stress response. SETTING AND
DESIGN: A prospective, double blind randomized trial comprising 130 ASA physical status class I and II patients posted for laparsoscopic cholecystectomy.
MATERIALS AND METHODS: Patients were randomized in to Group A and Group B. Group A received intravenous dexmedetomidine in a dose of 1 ug.kg-1, through an infusion pump 20 min prior to induction of anaesthesia. Group B subjects received oral pregabalin 150 mg. Parameters observed were vitals, discharge time, cortisol level, side effects if any.
RESULTS: Post intervention heart rate got reduced significantly in Group A and it remained low in comparison to baseline during whole peri-operative period. In Group B, immediate post-pneumoperitoneum heart rate, and post exubation heart rate was higher than baseline. Blood pressure (BP) decreased significantly post intervention in Group A which persisted till pneumoperitoneum. In Group B there was statistically significant rise in systolic, diastolic and mean blood pressure postpneumoperitoneum as compared to baseline blood pressure. Post-operative cortisol level was significantly higher than baseline values and the level is more in Group B.
CONCLUSION: Intravenous dexmedetomidine is more effective than oral pregabalin in attenuating perioperative stress response. Copyright:

INTRODUCTION

Laparoscopic surgery is one of the most important diagnostic and therapeutic tools in the modern surgical era. First successful laparoscopic cholecystectomy was performed by Phillipe Mouret in 1987, and since then, laparoscopy has become the gold standard method for cholecystectomy.[1] The benefits of laparoscopic techniques, such as less pain, early mobilization, minimal scar, and shorter hospital stay, have further increased its applications.[23] This minimally invasive procedure, however, requires pneumoperitoneum for adequate visualization and operative manipulation. The major problems during laparoscopic surgery are related to the cardiopulmonary effect of artificial pneumoperitoneum, systemic carbon dioxide absorption, and patient positioning.[24] Due to the requirement of steep head-up position, the chances and severity of unwanted hemodynamic responses such as hypertension and tachycardia are much higher in laparoscopic cholecystectomy when compared with other laparoscopic surgeries. The goal of anesthetic management in laparoscopic surgeries is to minimize the pneumoperitoneum induced hemodynamic responses along with adequate depth and pain control with the target of minimal stress response and early discharge. For these reasons, general anesthesia with tracheal intubation is the anesthetic technique of choice.[5] As laparoscopic surgeries gain importance, there was a surge in search for the drugs and techniques that attenuate the hemodynamic response of artificial pneumoperitoneum. Pneumoperitoneum response like laryngoscopy response is mediated by sympathetic overactivity, so most of the drugs studied so far to attenuate laryngoscopy response have been used with varied success rate to attenuate pneumoperitoneum response too, examples being fentanyl, volatile anesthetic agents, and esmolol.[67] Dexmedetomidine, an α2 adrenoceptor agonist, is gaining popularity for its sympatholytic, sedative, anesthetic-sparing, and hemodynamic-stabilizing properties without significant respiratory depression.[8] When administered intravenously, its effect starts in <5 min and the peak effect occur within 15 min the duration is around 60–120 min.[9] Pregabalin, a structural derivative of the inhibitory neurotransmitter γ aminobutyric acid, possess analgesic, anticonvulsant, anxiolytic, and sleep-modulating activities and is being used for above cited purpose.[1011] Pregabalin inhibits voltage-dependent calcium channels by binding to their auxiliary α2δ subunit site.[12] Besides being cheap, it can be administered orally after which it achieves peak plasma levels within 30 min to 2 h with mean of 54 min.[13] Both drugs are promising and are being used on the basis of choice of anesthesiologist as they have not been compared yet regarding their efficacy for the common goal of attenuation of hemodynamic and stress response. The aim of the current study was to find the better choice among two by comparing their efficacy in attenuating the undesired response to laryngoscopy, endotracheal intubation, and CO2 pneumoperitoneum and to evaluate whether they are effective in reducing endocrinal stress response too.

METHODOLOGY

The current study was performed as a prospective, randomized, double-blinded controlled trial after obtaining approval from the Institutional Ethical Committee and informed written consent from all the participants. The patients were 130 American Society of Anesthesiologists Physical Status Classes I and II patients, of age group 20–50 years, scheduled for elective laparoscopic cholecystectomy under general anesthesia. Patients with anticipated difficult intubation, allergic to any anesthetic medication, obesity, pregnant and lactating patients, and those taking sedatives, hypnotics, or antihypertensives were excluded from the study. For statistical analysis, researcher also excluded cases where laryngoscopy exceeded 15 s or a second attempt was performed, so were patients where laparoscopy time exceeded 90 min.

The sample size was calculated by power analysis of previous pilot studies keeping power at 90% and alpha error at 0.05. The exact calculated sample size for each group was 103 patients. Keeping in mind about intraoperative and postprocedure exclusion, the size was arbitrarily increased to 130.

After detailed preanesthetic evaluation, all selected patients under study were randomly divided into two groups (Group A and Group B) using computer-generated randomization, all the selected patients were shifted to the preoperative room where baseline heart rate and blood pressure (systolic, diastolic, mean) were recorded and a blood sample was collected for estimation of serum cortisol level. Serum cortisol was measured with an electrochemiluminescence immunoassay on a cobas analyzer (Roche Diagnostics, Mannheim, Germany). The normal reference range is 130–530 nmol.L-1 for 6–12 A.M.

To ensure blinding, all patients were administered both oral medication and intravenous infusion by medical staff unaware of the content of the medication. Participants of Group A received placebo capsule 90 min prior to induction with a sip of water followed by intravenous dexmedetomidine in a dose of 1 μg.kg-1 diluted in 100 mL normal saline over a period of 10 min, through an infusion pump which was started 20 min prior to induction of anesthesia. Group B patients received pregabalin 150 mg in capsule form with sips of water 90 min before induction followed by infusion of 100 mL saline over the period of 10 min with infusion pump. Vital signs were rerecorded in preoperative room at 10 min after oral administration and just after completion of intravenous infusion. On arrival in the operating room, monitors were attached and the patient's heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure oxygen saturation were recorded, neuromuscular monitor was attached to monitor ulnar nerve response.

Participants of both groups were premedicated with intravenous injection of ondansetron 4 mg, midazolam 1 mg, and fentanyl in the dose of 2 μg.kg-1. All the patients were preoxygenated with 100% oxygen for 5 min and then induction was done with intravenous injection of propofol in a dose sufficient for loss of verbal command, followed by injection vecuronium bromide (0.1 mg.kg-1) to provide neuromuscular blockade. The participants were ventilated by mask till neuromuscular monitor showed loss of second twitch in train of four sequences. Laryngoscopy was performed and trachea was intubated with appropriate size disposable cuffed endotracheal tube. Anesthesia was maintained with 66:33 N2O and O2 and intermittent bolus of intravenous vecuronium (1/4 of loading dose) as per requirement. Intraoperatively, isoflurane was administered in the dose range of 0.8–1.5 minimum alveolar concentration to maintain systolic blood pressure and heart rate within 20% of preoperative values. If upper dose limit of isoflurane was unable to maintain the vitals, intravenous bolus of fentanyl was administered in the dose of 20 μg per bolus. Patients were mechanically ventilated to maintain the end-tidal CO2 in the range of 35–40 mmHg. Upper limit of tidal volume was 12 mL.kg-1 and that of peak end-expiratory pressure used was 5 cm of water. Parameters observed intraoperatively were heart rate and blood pressure including mean arterial pressure at baseline, after premedication, after induction, immediately after intubation, just after creation of pneumoperitoneum and then 5, 10, and each 10 min thereafter. Decrease in heart rate (<50 bpm) was treated with intravenous bolus of atropine 0.5 mg. Decrease in MAP (mean arterial pressure) of more than 20% from baseline or systolic arterial pressure <90 mmHg was treated by increasing the intravenous fluid infusion rate or incremental doses of ephedrine 5 mg intravenous bolus. Requirement of bolus doses of fentanyl was also quantified. Patients requiring chronotropic (atropine) and vasopressor agents were noted and their hemodynamic data were not included for statistical comparison. After completion of surgery, residual neuromuscular block was reversed with appropriate intravenous doses of neostigmine (0.05 mg.kg-1) with glycopyrrolate (0.01 mg.kg-1), and extubation was performed when respiration was spontaneous and adequate. Postextubation, patient was kept in postanesthesia care unit, fully equipped to deal with any sort of emergency. Transfer from PACU to ward was based on Modified Alderete score [Table 1] which was estimated every 30 min.[14] A minimum score of 9 was used as a guide for discharge. Proportion of patients who achieved scores of 9 or more within the 1st postoperative hour, within 90 min, and within 2 h were quantified. A repeat blood sample was taken 1 h after completion of surgery for estimation of postoperative cortisol level.

Table 1

The Modified Aldrete Scoring System (for determining when patients are ready for discharge from the postanesthesia care unit)

The Modified Aldrete Scoring System
Criteria	Score
Activity (able to move voluntarily or on command)
4 extremities	2
2 extremities	1
0 extremities	0
Respiration
Able to deep breathe and cough freely	2
Dyspnea, shallow, or limited breathing	1
Apneic	0
Circulation
BP ± 20 mm of preanesthetic level	2
BP ± 20–50 mm of preanesthesia level	1
BP ± (>50) mm of preanesthesia level	0
Consciousness
Fully awake	2
Arousable on calling	1
Not responding	0
O2 saturation
Able to maintain O2 saturation >90% on room air	2
Needs O2 inhalation to maintain O2 saturation >90%	1
O2 saturation <90% even with O2 supplementation	0

BP=Blood pressure

All the data were expressed as mean and standard deviation for continuous data and number and percent for categorical data and proportion for proportionate data. Data were analyzed using Student's t-test for qualitative variables; two-tailed Dunnett test was used for cortisol and hemodynamic data. Categorical data were analyzed by using Chi-square or Fisher exact test as appropriate. P < 0.05 was considered as statistically significant. All statistical analyses were performed with SPSS, Version 22.0, IBM Corp Armonk, NY, USA.

RESULTS

The study enrolled 130 patients [Figure 1] of which three patients (1 of Group A and 2 of Group B) were excluded as laryngoscopy time exceeded 20 s. One patient of Group B was excluded as she required two attempts of laryngoscopy. In two patients of Group A, bradycardia occurred which was managed successfully by 0.5 mg of atropine intravenously, the hemodynamic data of these patients were excluded. Four patients of Group A were excluded further as the laparoscopy time exceeded 120 min. Three patients of Group B were also excluded on the basis of excess laparoscopy time. The final numbers of patients for the study were 58 in Group A and 59 in Group B.

Figure 1

Consort flow diagram

The demographic pattern (age, weight, and sex) was comparable between the groups [Table 2]. The mean duration of laryngoscopy and laparoscopy was similar in both groups.

Table 2

Demographic data

Variables	Group A (n=58)	Group B (n=59)	P
Age (years)	44.56±7.81	42.12±8.11	0.10
Weight (kg)	52.55±9.64	54.25±10.69	0.36
Sex (male:female)	30:28	31:28
Duration of laryngoscopy (s)	11.48±2.83	10.83±3.04	0.28
Duration of laparoscopy	39.78±12.56	43.41±10.12	0.087

In the analysis of hemodynamic variables, the baseline heart rate was comparable in both the groups. When compared to baseline, postintubation heart rate was lower in Group A than Group B, and the difference was, however, not significant statistically. In Group B also, there was no significant difference between baseline heart rate and immediate postintubation heart rate [Table 3]. In Group B, immediate postpneumoperitoneum heart rate (P = 0.001) and mean intraoperative heart rate were significantly higher than baseline heart rate. In Group A, the heart rate remains comparable to baseline heart rate in whole perioperative period [Table 3].

Table 3

Comparison of periodic perioperative heart rate (bpm) and mean arterial pressure (mmHg) at critical periods from baseline

Time intervals	Heart rate		MAP
	Group A (n=58)	Group B (n=59)	Group A	Group B
Baseline (B)	80.45±12.72	78.52±11.88	92.63±8.78	91.45±7.81
Immediately postintervention	71.31±8.12	80.96±10.14	82.31±8.12	89.16±9.32
Postinduction	65.45±10.23	74.59±9.72	73.81±9.79	81.42±8.74
Immediately PI	78.12±9.87	81.95±10.92	83.57±10.95	93.82±10.98
P (PI values compared with baseline)	2.33	0.10	0.023*	0.341
Immediately PP	79.45±11.80	91.33±11.59	89.79±10.47	96.45±9.53
P (PP values compared with baseline)	0.9	<0.001**	0.12	0.025*
IO mean	78.01±12.45	82.86±10.37	86.45±11.29	88.67±10.98
P (IO values compared with baseline)	3.44	0.036*	0.09	1.45
Immediate postextubation	78.50±8.67	83.41±9.24	86.18±10.01	96.92±11.20

*Significant statistically, **Highly significant statistically. PI=Postintubation, PP=Postpneumoperitoneum, IO=Intraoperative, MAP=Mean arterial pressure

Systolic, diastolic, and mean blood pressure decreased significantly postintervention in Group A [Figure 2]. In Group B, intervention had not shown any significant impact on blood pressure [Figure 2]. Postintubation, there was a rise in systolic, diastolic, and mean blood pressure in Group B as compared to baseline, and on statistical analysis, the rise was significant in systolic blood pressure only contrary to this, in Group A, the fall in blood pressure which is significant statistically persisted postintubation too. Pneumoperitoneum increased blood pressure in both groups; the rise in Group A patient's blood pressure was such that the mean blood pressure becomes comparable to baseline blood pressure [Figure 2 and Table 3]. In Group B, there was statistically significant rise in systolic, diastolic, and mean blood pressure postpneumoperitoneum as compared to baseline blood pressure. Intraoperative mean arterial pressure was significantly higher in Group B as compared to Group A. Vasopressor was not required in any patient of both groups.

Figure 2

Graphical representation of variation in perioperative blood pressure

Proportion of patients achieved postoperative discharge criteria in 1st h (78.4% in Group A vs. 38.9 in Group B) was significantly higher in Group A when compared with Group B. Almost all patients (98%) of Group A achieved discharge criteria by 90 min, in comparison, only 66% of Group B patients achieved the discharge criteria by 90 min, the difference was highly statistically significant [Table 4]. All patients of Group A achieved discharge criteria by 2 h, and 96.6% (57 out of 59) of Group B patients achieved discharge criteria, the difference was not significant statistically (P = 0.071).

Table 4

Proportion of patients achieving discharge criteria

Time interval	Group A (n=58)	Group B (n=59)	P
Within 1st hour	42	23	0.0002
Within 90 min	57	39	0.00006
Within 2 h	58	57	NA

NA=Not applicable

The mean baseline serum cortisol level was comparable in both groups and is in normal range [Table 5]. The mean postoperative cortisol level was significantly higher than baseline values and the rise is more in Group B as compared to Group A (P = 0.0001).

Table 5

Mean cortisol level

Cortisol level	Group A	Group B	P
Baseline (nmol/L)	409±54	389±64	0.06
Postoperative (nmol/L)	502±71	673±89	0.0001
P	0.013	0.001

Five patients of Group B required fentanyl bolus, which was required in two patients of Group A [Table 6], but the difference was not significant (P = 0.25). Two patients of Group A reported nausea in postoperative period; in comparison, nine patients of Group B reported nausea and the difference was significant statistically (P = 0.01). Vomiting was not reported in any of the patients of either group.

Table 6

Side effects and additional drug requirement

Side effects	Group A (n=58)	Group B (n=59)	P
Nausea	2	9	0.014
Vomiting	0	0	NA
Bradycardia	2	0	0
Hypotension	0	0	NA
Fentanyl requirement (number of patients requiring it at least once)	2	5	0.25

NA=Not applicable

DISCUSSION

The current study was conducted to determine the adjuvant of choice for attenuating hemodynamic response in laparoscopic cholecystectomy. Dexmedetomidine effectively attenuated the rise of heart rate and mean arterial blood pressure indicating inactivation of catecholamine that is further supported by only little rise in postoperative cortisol level. Premedication with pregabalin 150 mg also effectively attenuates laryngoscopy response, but postpneumoperitoneum tachycardia increased blood pressure along with mildly increased postoperative cortisol level suggest its efficacy in preventing postpneumoperitoneum sympathetic response is poor.

The mechanisms underlying the hemodynamic responses to laryngoscopy are not completely understood, although a reflex sympathetic discharge caused by stimulation of the upper respiratory tract seems to be the main factor.[4] This hypothesis is supported by the previous studies which demonstrated that hemodynamic responses to tracheal intubation are associated with an increase in plasma catecholamine concentrations[1516] and are attenuated by β-adrenergic blockade.[17] The hemodynamic response to CO2-induced pneumoperitoneum is via two different mechanisms:[18]

Mechanical effects relating to increased intraperitoneal pressure

Chemical effect of CO2 used for insufflation.

The pneumoperitoneum compresses the inferior vena cava, which leads to reduction in venous return leading to decrease cardiac output and increase in the central venous pressure, resulting in increased vascular resistance in the arterial circulation.[19] Another effect is tachycardia, which is secondary to increased sympathetic discharge, hypercarbia, and decreased venous return. As compared to open cholecystectomy, laparoscopic cholecystectomy generates less prominent stress response and smaller metabolic interference.[2] Stress response markers, namely, epinephrine, norepinephrine, and interleukin-6 (IL-6), however, rise (mild to moderate) in laparoscopic cholecystectomy too.[20]

To reduce the incidence and severity of the hemodynamic responses of laryngoscopy and pneumoperitoneum, many pharmacological methods were evaluated either in the premedication or during induction. The promising agents include lidocaine, esmolol, sodium nitroprusside, and fentanyl. Short-acting opioids, remifentanil (1.0 μg.kg-1), alfentanil (10–20 μg.kg-1), or fentanyl (1.0–1.5 μg.kg-1) were reported to have the most promising effect on hemodynamic response to laryngoscopy and tracheal intubation, but they prolonged the recovery time.[67]

The agents used in the current study possesses several properties to make them valuable premedicating agents for attenuating the hemodynamic response of laryngoscopy. Dexmedetomidine produces anxiolysis, sedation, potentiation of analgesic, and sympatholysis via hyperpolarization of noradrenergic neurons and suppression of neuronal firing in the locus cerelous, thereby limiting systemic noradrenalin release. Previous studies had proved its effectivity in reducing stress response.[21] Pregabalin, (S)-3-(aminomethyl)-5-methylhexonic acid a Food and Drug Administration-approved agent, for treating partial seizures, general anxiety disorders, and neuropathic pain acts at presynaptic calcium channels to modulate neurotransmitter release in the central nervous system. White et al.[22] have shown that oral pregabalin in dose of 75 mg was not effective in attenuating preoperative anxiety, and at a dose of 300 mg, produced increased level of sedation after surgery. Based on the result of the previous study, the dose of pregabalin was chosen as 150 mg.[12]

Regarding dexmedetomidine, the findings of the current study resemble that of Aho et al. who concluded that patients receiving dexmedetomidine before surgery had significantly lower intraoperative catecholamines and cortisol levels compared with those who did not receive the drug before surgery.[23]

Another important aspect of any premedicating agent is that it should not prolong the discharge time and should lack any untoward side effects. In this parameter also, the current study finds dexmedetomidine to be better than pregabalin. As per the current study, pregabalin in the dose of 150 mg delays discharge when compared with dexmedetomidine, and this can be due to its side effects such as headache, vertigo, and drowsiness which can be present after single dose of pregabalin.[24] Agarwal et al.[25] also reported similar findings with pregabalin, when they studied the drug for attenuation of postopearative pain. The current study, however, correlates with the conclusion laid down by Singh et al. who concluded pregabalin to be effective in attenuating preoperative anxiety and stress response to endotracheal intubation, and they, however, did not measure any chemical markers of stress or the study took pneumoperitoneum into consideration.[11]

In the current study, bradycardia was the only side effect reported (in two patients) with dexmedetomidine which responded well with atropine, the hemodynamic data of these patients were not included as it may affect the overall mean heart rate and result in bias. With pregabalin, nausea was the most prominent side effect, though none of the patients reported vomiting. Agarwal et al.[25] also reported significant nausea and vomiting in the pregabalin group; they, however, did not administer ondansetron, which was administered to every patient of the current study.

Tumor necrosis factor-alpha, heat-shock protein, catecholamines, and IL-1 are better markers of stress response which were not measured and thus included as limitations of the current study. Further, the current study was undertaken in noncardiac and nonhypertensive patients, so the results of current study cannot be applied over hypertensive and cardiac patients.

CONCLUSION

Intravenous dexmedetomidine 1 μg.kg-1 is more effective than oral pregabalin 150 mg in attenuating perioperative stress response, including hemodynamic response to laryngoscopy and pneumoperitoneum.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.