Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

BACKGROUND: Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. SUBJECTS AND METHODS: Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test.
RESULTS: The HR and MAP were found to be higher in Group A. The difference was statistically significant (P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant (P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant (P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups.
CONCLUSIONS: Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

INTRODUCTION

Laparoscopic pyeloplasty has gained widespread popularity as a definitive treatment for significant pelvi-ureteric junction obstruction owing to its minimally invasive nature, reduced pulmonary dysfunction, quicker recovery, and shorter hospital stay.[1] However, intraoperative hemodynamic changes may occur due to intra-abdominal carbon dioxide (CO2) insufflation and kidney handling leading to renin release.[2] Stress responses encompass a series of endocrinal, immunological, and hematological effects.[3]

Many drugs, namely, alpha-2 adrenergic receptors agonists, high doses of opioids, and β-blockers have been tried in the past to decrease stress responses during laparoscopic surgery. By reducing the sympathoadrenal and cardiovascular responses caused by noxious surgical stimuli, the alpha-2 agonists inhibit the stress responses mediated by the sympathetic nervous system. Alpha-2 adrenoceptors’ activation results in sympatholysis, inhibition of renin release, and decrease in insulin release from the pancreas. Clonidine, a centrally acting partial alpha-2 adrenergic agonist (220:1/α2:α1), has been used to decrease stress responses. Dexmedetomidine is a selective and potent α2-adrenergic agonist. The α2/α1 selectivity of dexmedetomidine is i1600 times higher than that of clonidine.[4]

There has been limited research on evaluating the stress responses during laparoscopic urological procedures with majority of studies concentrating on nephrectomy.[56] Laparoscopic pyeloplasty in experienced hands could last for 3–4 h. There have been evidences that prolonged laparoscopic procedures have been found to be associated with increased stress responses. Dexmedetomidine decreases renin release thereby imparting hemodynamic stability.[7] Cortisol levels have been shown to be decreased by dexmedetomidine.[89]

The primary aim of this study was, therefore, to evaluate and to compare the efficacy of the two different doses of dexmedetomidine in reducing the stress responses in patients undergoing laparoscopic pyeloplasty.

SUBJECTS AND METHODS

The study was initiated after receiving approval from the Institutional Ethics Committee of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India (Decision no: IEC-2013-06-MD-67), and the written informed consent from the patients. The study was conducted from March 2013 to February 2014. It was a prospective, randomized, double-blind, placebo-controlled clinical study. Ninety patients in American Society of Anaesthesiologist physical status I and II, between 18 and 60 years, of either sex and posted for conventional laparoscopic pyeloplasty by same surgeon under general anesthesia were included in the study. Elderly, diabetic, chronic hypertension, patients on drugs such as beta blockers or calcium channel blockers, pregnant or lactating women, patients with abnormal serum creatinine and blood urea nitrogen (BUN), and patients with a history of allergy to drugs particularly α2 agonists were excluded from the study.

The patients were randomly allocated into three groups by computer-generated randomized slips into three groups of thirty patients each. Surgery was scheduled as first case in the morning at 9 AM. The study solutions were prepared by an anesthesiologist who was not participating in the study. In case of any adverse event related to the drug, the anesthesiologist who prepared the drug was authorized to reveal the drug. In all groups, loading doses were calculated and diluted in 10 ml solution to be given over 10 min. The infusion solutions of dexmedetomidine for the maintenance were prepared in normal saline at a concentration which could deliver the intended dose of the allocated group at the rate of 10 ml/h through Injectomat agile® (Fresenius Kabi, USA) syringe pump infusion.

All patients were premedicated with oral lorazepam 0.04 mg/kg and ranitidine 150 mg night before and 2 h before surgery. On arrival to the operation room, intravenous access was achieved with 18 G venous cannula under local anesthesia with 2% lignocaine. Monitoring consisted of 5 lead electrocardiography, pulse oximeter, noninvasive blood pressure (BP), temperature, and end-tidal CO2.

Following preoxygenation, patients were given fentanyl 2 mcg/kg, intravenously. The patients in Group A received 10 ml of normal saline over 10 min followed by infusion at 10 ml/h. The patients in Group B received 1 mcg/kg of dexmedetomidine as loading dose followed by maintenance infusion of 0.7 mcg/kg/h. The patients in Group C received 0.7 mcg/kg of dexmedetomidine as loading dose followed by maintenance infusion of 0.5 mcg/kg/h. Heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels were used as markers of stress responses. All infusions were stopped 10 min before extubation.

After giving dexmedetomidine or normal saline according to the group, thiopentone was used as an induction agent in the dose of 4 mg/kg. For facilitating endotracheal intubation, vecuronium 0.12 mg/kg was given, and after 3 min of bag and mask ventilation with 100% O2, endotracheal tube was inserted and the patient was connected to mechanical ventilator on volume control mode. Isoflurane was used as maintenance agent to obtain a concentration of one minimum alveolar concentration. Patients were placed in lateral decubitus position. Top-up doses of vecuronium 0.01 mg/kg were repeated accordingly. Fentanyl 1 mcg/kg was repeated every 30–40 min. Patients in all groups received normal saline as intravenous fluid during anesthesia. Intra-abdominal pressure for laparoscopic pyeloplasty was set between 12 and 14 mmHg. Patients were mechanically ventilated with a mixture of 50% oxygen in air, tidal volume of 8–10 ml/kg, and respiratory rate was adjusted to maintain normocarbia.

HR and MAP were measured at before starting the induction, before and 1 min after the intubation, at 5 min interval for 30 min, and subsequently after every 15 min till the end of surgery. These parameters were also measured at the time of extubation, 10 min, 1 h, and 2 h after the extubation. Blood glucose levels were measured by glucometer (Abbott Optium Xceed) at baseline, preinduction, and 1 min postintubation followed by hourly serial monitoring. Blood glucose levels were also measured at the time of extubation and 2 h postextubation. Serum cortisol was measured on the day of surgery at 8 AM, 1 min postintubation, intraoperatively during handling of kidney, and 2 h postextubation.

At the end of the surgery, the neuromuscular blocking agent was antagonized with a combination of neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Patients were transferred to the postanesthesia care unit after the completion of surgery.

The sample size was calculated using Power Analysis and Sample Size version 2008 (PASS-2008) manufactured by NCSS, LLC. Sample size was calculated at minimum 80% power and 0.05 level of significance, with relative mean difference of 20% of control group with respect to treatment groups. Results were calculated using statistical package for the social sciences 20.0 (SPSS Inc., Chicago, IL, USA). Descriptive study in the form of mean, standard deviation, standard error, and confidence interval was done. One-way analysis of variance test was applied for statistical analysis. Multiple comparisons between groups were done with post hoc Bonferroni test. P < 0.05 was considered statistically significant.

RESULTS

A total of ninety patients were enrolled in the study and divided into three groups. Patients among three groups were comparable in terms of demographics (sex, age, and weight), duration of anesthesia and surgery [Table 1]. Basal renal parameters in the form of serum creatinine and BUN were within normal range.

Table 1

Demographic (mean±standard deviation) of the patients among groups

HR was found to be statistically significant (P < 0.05) and higher in Group A as compared to Groups B and C during intubation, insufflations of CO2, and extubation [Figure 1]. The HR values were statistically insignificant and comparable throughout perioperative phase in Groups B and C [Figure 1].

Figure 1

Heart rate showing mean and confidence interval among three groups. # = P < 0.05 when Group A was compared to Group B, ! = P < 0.05 when Group A was compared to Group B, ↓ = P < 0.05 when Group B was compared to Group C

The MAP was comparable and statistically insignificant among all the groups before induction phase. During intubation, insufflations of CO2, and extubation, the values were statistically significant (P < 0.05) and higher in Group A as compared to Groups B and C [Figure 2]. The MAP values were statistically insignificant and comparable throughout perioperative phase in Groups B and C.

Figure 2

Mean arterial pressure showing mean and confidence interval among three groups. # = P < 0.05 when Group A was compared to Group B, ! = P < 0.05 when Group A was compared to Group B, ↓= P < 0.05 when Group B was compared to Group C

Preinduction blood glucose levels were comparable among the three groups. Blood glucose levels at postintubation were statistically significant (P < 0.05) and higher in Group A when compared with Groups B and C while it was comparable and statistically insignificant between Groups B and C [Figure 3]. Blood glucose levels values at 1 h, 2 h, and 3 h intraoperatively were comparable and statistically insignificant among the three groups. Blood glucose levels were statistically significant (P < 0.05) and higher at extubation and at 2 h postextubation in Group A in comparison with Groups B and C while these were comparable and statistically insignificant in Groups B and C [Figure 3].

Figure 3

Blood sugar showing mean and confidence interval among three groups. # = P < 0.05 when Group A was compared to Group B, != P < 0.05 when Group A was compared to Group B, ↓ = P < 0.05 when Group B was compared to Group C

The difference in baseline value (8 AM) of serum cortisol was statistically insignificant among the groups. Serum cortisol at postintubation, at middle of the surgery, and 2 h postextubation was statistically significant (P < 0.05) and higher in Group A when compared with Groups B and C while it was comparable and statistically insignificant in Groups B and C [Figure 4].

Figure 4

Serum cortisol showing mean and confidence interval among three groups. # = P < 0.05 when Group A was compared to Group B, != P < 0.05 when Group A was compared to Group B, ↓ = P < 0.05 when Group B was compared to Group C

DISCUSSION

Our study was performed on patients undergoing laparoscopic pyeloplasty. This surgical population was chosen because the surgery is standardized and common. Laparoscopic surgeries cause major hemodynamic alterations during induction of anesthesia, creation of pneumoperitoneum, and at extubation. Stress response to surgery encompasses a wide range of endocrinological, immunological, and hematological effects. Endocrine responses to surgery are characterized by increased secretions of pituitary hormones and activation of sympathetic nervous system. Excitation of the hypothalamus during stress results in the secretion of adrenocorticotropic hormone which in turn initiates sudden increase in cortisol level.[3]

Perioperative period is a stressful period, and dexmedetomidine is a useful drug to decrease stress responses. Dexmedetomidine has been used by previous researchers as loading dose of 1 mcg/kg over 10 min, followed by maintenance infusion at 0.2–0.7 mcg/kg/h. Our study involves the use of dexmedetomidine in two different doses among two groups - 1 mcg/kg over 10 min, followed by maintenance infusion at 0.7 mcg/kg/h or other one being 0.7 mcg/kg as loading dose followed by maintenance infusion of 0.5 mcg/kg/h. Renal functions in the form of serum creatinine, BUN, and urine output were within normal range in our set of patients. Metabolites of dexmedetomidine biotransformation are excreted in the urine (about 95%). The pharmacokinetics of dexmedetomidine in participants with severe renal impairment (creatinine clearance <30 ml/min) is not altered relative to healthy controls.[10] Intraoperative use of dexmedetomidine infusion has showed insignificant difference with renal functions on percutaneous nephrolithotomy.[7] Hence, dexmedetomidine dose adjustment was not needed in our study inspite of patients having the possibility of renal dysfunction.

Our study showed that HR and MAP were found to be higher in Group A. The difference was statistically significant (P < 0.05) during intubation, CO2 insufflation, and extubation when compared with Groups B and C. However, HR and MAP were similar in dexmedetomidine groups.

Dexmedetomidine causes central sympatholytic and peripheral vasoconstrictive effects. Bajwa et al.[11] showed decrease in BP and HR by administering intravenous 1 mcg/kg dexmedetomidine at induction. Basar et al.[12] demonstrated reduction in HR by administering 0.5 mcg/kg of dexmedetomidine at induction. Kaya et al.[13] showed decreased HR and MAP compared to control group when dexmedetomidine was used in a dose of 1 mcg/kg as premedication. Dexmedetomidine when administered with a loading dose of 1 mcg/kg and maintenance of 0.7 mcg/kg/h suppresses the increase in BP due to anesthetic induction and also blunts the cardiovascular response to tracheal intubation.[14]

Dexmedetomidine at 1 mcg/kg loading dose, followed by maintenance with 0.5 mcg/kg/h showed decrease in HR and BP when compared to placebo.[151617] In laparoscopic cholecystectomy, when dexmedetomidine was used at a rate of 0.2 mcg/kg/h, HR and BP were significantly decreased after intubation and throughout the period of pneumoperitoneum when compared with placebo.[18] In laparoscopic surgery, dexmedetomidine when administered with a loading dose of 1 mcg/kg and maintenance of 0.2 mcg/kg/h showed decrease in BP and HR when compared with placebo.[19] In laparoscopic cholecystectomy, when dexmedetomidine was used at a rate of 0.2 mcg/kg/h and 0.4 mcg/kg/h, HR and BP were significantly lower when compared with placebo, and hemodynamics was statistically better in 0.4 mcg/kg/h group.[20] Dexmedetomidine infusion in the dose of 1 mcg/kg as bolus over 10 min and 0.5 mcg/kg/h intraoperatively as maintenance dose controlled the hemodynamic stress response in patients undergoing laparoscopic surgery.[21] Previous researchers mostly used dexmedetomidine in laparoscopic cholecystectomy, laparoscopic hysterectomy, or laparoscopic nephrectomy. We could not find any study comparing hemodynamic responses by perioperative use of two different doses of dexmedetomidine in laparoscopic pyeloplasty surgeries. Characteristics of this surgical population include a prolonged duration of surgery, more hemodynamic variability due to kidney handling, and lateral decubitus position.

The perioperative period is marked by decrease in insulin concentration and significant increase in insulin resistance leading to increased glucose levels. In our study, when dexmedetomidine groups were compared to control group, blood sugar levels were less after intubation, during extubation, and 2 h postextubation. Blood glucose levels values at 1 h, 2 h, and 3 h intraoperatively were comparable and statistically insignificant among the three groups. Dexmedetomidine when used intramuscularly in dose of 1 mcg/kg, there were no significant differences between the groups in the blood glucose levels.[13] A previous study[15] has showed no significant difference in blood glucose levels and insulin levels. However, one study showed significant difference in blood glucose levels during postoperatively in 1 h while there was no significant difference during 30 min postintubation and 6 h postoperatively.[16]

Release of corticotropin from pituitary stimulates cortisol secretion from adrenal cortex. Cortisol secretion from adrenal cortex increases rapidly after start of surgery. Our study investigated serum cortisol levels at various time intervals, and we found significant reduction in serum cortisol levels at postintubation, midsurgery, and 2 h postextubation in either of the dexmedetomidine groups.

Increase in serum cortisol in response to surgery was more pronounced in emergency procedure when compared to elective surgery.[22] Intraoperative infusion of 0.4 mcg/kg/h dexmedetomidine showed serum cortisol level to be significantly lower when compared with control group in the postoperative period.[9] Dexmedetomidine when used intramuscularly in dose of 1 mcg/kg, serum cortisol levels showed insignificant differences between the groups.[13]

Our study has some limitations. The stress response actually includes metabolic, hormonal, and immunological responses, but we studied only a part of this response in the form of a few hormones such as cortisol and insulin. We have also not incorporated depth of anesthesia monitor.

CONCLUSIONS

The results of our study showed that the perioperative use of dexmedetomidine decreases stress response and provides good condition for the maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.