A Comparative Study of Modulation of Neuroendocrine Stress Response by Dexmedetomidine versus Fentanyl Premedication during Laparoscopic Cholecystectomy.

INTRODUCTION: Surgical stress is the systemic response to surgical injury. Analyzing these surgical stress responses and pharmacologically modulating them can be of immense use to an anesthetist for optimal patient care. AIM: The aim of the present study was to investigate the influence of dexmedetomidine and fentanyl premedication on the modulation of neuroendocrine stress response during laparoscopic cholecystectomy under general anesthesia.
METHODS: After obtaining approval from the institutional ethical committee [Date - 05/11/2020, Ethical Clearence Number - 133/2018], 60 patients undergoing laparoscopic cholecystectomy under general anesthesia were randomized into three study groups of 20 patients each. Group D patients were given intravenous (i.v.) dexmedetomidine 1 μg.kg-1, Group F patients fentanyl 2 μg.kg-1 and Group C patients 10 mL of normal saline. All patients received the same anesthetic drugs and surgical procedure. Patients were assessed for changes in hemodynamic parameters such as heart rate (H) and mean arterial pressure (MAP). Blood samples were analyzed for glucose, serum albumin, C-reactive protein (CRP), and serum cortisol levels at various time intervals.
RESULTS: H and MAP differed among the groups after intubation, 5 min after pneumoperitoneum (POT), and 10 min after POT. The increase in these parameters from their baseline values was less in the dexmedetomidine group when compared to other groups. Among the biological markers, the increase in serum cortisol levels and decrease in albumin levels could be detected 6 h after induction while blood glucose levels rose immediately after the incision. CRP levels started significantly rising only after 24 h of induction. All these changes were much less pronounced in patients receiving dexmedetomidine premedication as compared to other groups.
CONCLUSION: i.v. dexmedetomidine 1 μg.kg-1 is better than injection fentanyl 2 μg.kg-1, in the modulation of neuroendocrine response in patients undergoing laparoscopic cholecystectomy under general anesthesia. Copyright:

INTRODUCTION

Surgical stress is the systemic response to surgical injury. Anxiety, metabolic, neurohumoral, and immunological changes are some of the complex stress responses associated with surgical stress.[12]

Neuronal activation of the hypothalamic–pituitary–adrenal axis is the primary reason behind all the hormonal changes following surgical stress. In general, the magnitude and duration of the response are proportional to the surgical injury and the development of complications.

Laparoscopic cholecystectomy has emerged as a gold standard surgery for cholelithiasis.[3]

Although laparoscopy cholecystectomy is a low-stress level surgery with fewer pulmonary complications and more rapid convalescence, is inadvertently associated with increased hemodynamic stress responses.[34] These hemodynamic changes can be attributed to the creation of pneumoperitoneum, potential for systemic absorption of carbon dioxide, and reverse Trendelenburg position.[4]

The choices of premedication and anesthetic techniques to decrease the stress response to surgery are of great importance, as an anesthesiologist. Dexmedetomidine, a highly selective α2 adrenoceptor agonist, and fentanyl, a phenylpiperidine-derivative synthetic opioid agonist, are some of the many drugs used to decrease stress responses to surgery.

The aim of the present study is to investigate the influence of dexmedetomidine and fentanyl premedication on the modulation of neuroendocrine stress response during laparoscopic cholecystectomy under general anesthesia.

METHODS

This double-blinded prospective randomized study was conducted after institutional ethical committee approval. Informed consent was obtained from all recruited adult patients posted for laparoscopic cholecystectomy of duration <2 h, patients’ physical status ASA classes I and II between the age group of 19 and 65 years, and body mass index 18.5–25 kg.m − 2. Pregnant patients or patients suffering from cardiac, pulmonary, hepatic, renal, or metabolic disorders or receiving medications which affect sympathetic response or hormonal secretions were excluded from the study.

Sample size calculation was done based on 95% confidence interval, 5% alpha error using G power Software, and a total of 60 patients were selected. The patients were then randomized into the study groups of 20 patients each according to computer-generated code [Figure 1]. The drug preparation was done by an anesthesiologist who was blinded to the study protocol and the observer was kept blinded about the randomization schedule of the study protocol.

Figure 1

Consort flow diagram

All patients were premedicated with tablet alprazolam 0.25 mg the night before surgery and on the day of surgery at 6 am with small sips of water. On arrival to the operation room, fluids through 18 G intravenous (i.v.) cannula was started and hemodynamic monitoring was attached including noninvasive blood pressure measurements, five-lead electrocardiogram monitor, and finger pulse oximetry. All the patients were premedicated with glycopyrrolate 10 μg.kg−1 i.v. and midazolam 0.05 mg.kg − 1 i.v. The patient in the three study groups received the drug as follows:

Group D (n = 20) dexmedetomidine 1 μg.kg − 1 i. v. over a 10 min period before induction of general anesthesia.

Group F (n = 20) fentanyl 2 μg.kg − 1 i. v. over a 10 min period before induction of general anesthesia.

Group C (n = 20) 10 mL of normal saline i.v. over a 10 min period before induction of general anesthesia.

After preoxygenation with 100% oxygen for 3 min, the anesthesia was induced with propofol i.v. (2 mg.kg−1) and tracheal intubation was facilitated by vecuronium (0.1 mg.kg−1) i.v. Anesthesia was maintained with isoflurane 1%–1.5% and 60% nitrous oxide in oxygen and supplemental doses of vecuronium (0.01 mg.kg−1).

At the end of the surgery, the neuromuscular block was reversed with neostigmine 0.05 mg.kg − 1 and glycopyrrolate 0.4 mg.kg−1 i.v., and the trachea was extubated when respiration became adequate and the patient was able to obey verbal commands.

All patients were assessed for changes in hemodynamic parameters of heart rate and mean arterial pressure (MAP) before premedication (baseline), before induction (during premedication), after intubation, and after pneumoperitoneum (POT), followed by every 5 min for 30 min thereafter every 15 min till the end of surgery and 10 min after extubation. Blood samples were analyzed for blood glucose, serum albumin, C-reactive protein (CRP) levels preoperatively (baseline), just after incision, at 6 h after anesthesia induction, and at 24 h after induction. Serum cortisol levels were analyzed preoperatively and at 6 h after anesthesia induction.

The results were presented in frequencies, percentages, and mean ± standard deviation. The Chi-square test was used to compare categorical variables among the groups. The one-way analysis of variance test, followed by Tukey's post hoc tests was used to compare continuous variables among the groups. P < 0.05 was considered statistically significant. All the analysis was carried out on SPSS 16.0 version (Inc., Chicago, IL, USA).

RESULTS

All the groups were found comparable in terms of demographic profile, anthropometric parameters, duration of surgery, and ASA physical status [Table 1].

Table 1

Demographic characteristics and operative data

Characteristics	Group D	Group F	Group C	P value
Age (years) (Mean±SD)	32.74±9.07	34.80±10.38	36.15±11.74	0.11
BMI (kg/m2) (Mean±SD)	22.88±1.79	22.72±1.61	23.59±1.30	0.19
Duration of surgery (min) (Mean±SD)	36.00±8.67	39.00±8.52	37.50±8.95	0.55
ASA (I: II)	20:0	19:1	18:2	0.34
Sex (Male: Female)%	15:85	15:85	20:80	0.88

BMI=Body mass index, SD=Standard deviation, P<0.05 Significant

There was a significant (P < 0.05) increase in heart rate (H) and MAP in all the groups after intubation. At 5 min after POT, H further increased in each group and achieved maximum mean value for that group, being 108.60 ± 5.16 bpm in Group D, 119.10 ± 7.65 bpm in Group F, and 128.65 ± 6.76 bpm in Group C. Similarly, MAP peaked at 5 min after POT and achieved maximum mean value for that group, being 88.05 ± 3.54 mmHg in Group D, 95.75 ± 3.78 mmHg in Group F, and 99.10 ± 3.64 mmHg in Group C. On comparing Group D with Group F at 5 min after POT, the increase in heart rate (P = 0.001) and MAP (P = 0.001) was significantly less in Group D. Both the parameters finally stabilized and became comparable after 15 min of POT among all the groups.

Blood glucose concentration significantly increased after incision and remained elevated postoperatively till 6 h of induction in all groups. This increment was significantly more pronounced after the fentanyl premedication versus dexmedetomidine premedication (122.00 ± 13.29 vs. 106.50 ± 6.88 mg.dL − 1; P < 0.05 just after incision)

There was a significant (P = 0.001) decrease in serum albumin from baseline in all the groups at 6 h after induction which persisted till 24 h. The drop from the baseline was significantly less marked in the dexmedetomidine group versus the fentanyl group (46.86 ± 3.41 vs. 40.90 ± 2.92 g.L − 1; P < 0.05).

CRP and serum cortisol levels increased after 24 h and 6 h of induction, respectively. Cortisol levels were significantly higher for the fentanyl group than in the dexmedetomidine group (63.99 ± 12.31 vs. 41.30 ± 15.35 μg.kg−1, P = 0.001). The mean CRP value at 24 h for dexmedetomidine group was much lower than fentanyl group (20.49 ± 5.95 mg.L−1 vs. 29.92 ± 5.70 mg.L−1, P = 0.001).

Serum albumin, cortisol, and CRP levels were not found to be significant between Group F and Group C at all time intervals, thus were comparable.

DISCUSSION

In our study, we tried to determine the modulation of stress response in laparoscopic cholecystectomy by evaluating biological markers and hemodynamic parameters. We found that the H and MAP started significantly increasing (P = 0.001) after intubation in all the groups [Figures 2 and 3] and normalized after 10 min of pneumoperitoneum. These changes were probably due to sympathetic stimulation caused by laryngoscopy, intubation, and CO2 insufflation. When statistically analyzing the hemodynamic parameters between these groups, there was lower range of increase seen in Group D when compared to Group F. Gupta et al.[5] in their study found that in dexmedetomidine group, the heart rate (maximum mean value = 78.92 + 7.95 bpm) was significantly (P < 0.05) less elevated than fentanyl group (mean = 91.84 + 10.19 bpm), consistent with our study. Srivastava et al.[6] too reported no significant increase in MAP in group dexmedetomidine versus group esmolol (85.21 ± 7.95 vs. 98.07 ± 7.61 mmHg). Jain et al.[7] and Kataria et al.[8] compared dexmedetomidine premedication with pregabalin and fentanyl, respectively. They arrived at a similar conclusion, that is, the increase in heart rate in the dexmedetomidine group was less as compared to other group.

Figure 2

Comparison of heart rate among groups

Figure 3

Comparison of mean arterial pressure among groups

Hyperglycemic changes seen after incision [Table 2] were likely to be induced secondary to pneumoperitoneum. The influence of soluble carbon dioxide on the carotid and aortic chemoreceptor enhances the sympathetic outflow mediated by afferent impulses to subcortical centers.[9] Stimulation of sympathetic nervous activity elevates blood glucose primarily by stimulating hepatic glycogenolysis and suppression of insulin secretion. The increment in glucose levels seen in our study was less pronounced in Group D than Group F similar to the study by Gupta et al.[5] In a similar study by Yacouta et al., blood glucose levels were less elevated after the dexmedetomidine group versus placebo (99.80 ± 10.78 vs. 142.07 ± 14.44 mg.dL − 1, P = 0.000). Protein metabolism is significantly disturbed after any kind of traumatic event, for example, surgery, sepsis, and burn injuries;[1011] albumin has been identified as a reliable indicator of this process.[111213] Albumin drop can be due to impaired hepatic albumin synthesis, to facilitate the production of these acute-phase molecules (CRP, fibrinogen, and macroglobulin) needed in the host defense process[1114] or consumption of protein to favor glyconeogenesis[15] or due to sequestration into the third space. Albumin drop was evident only after 6 h of induction [Table 3], in our study. The drop in albumin levels from the baseline value was only 2.05 g.L−1 in Group D as compared to much larger drop of 7.56 g.L−1 in Group F. Hübner et al.[16] found out significant (P < 0.001) postoperative albumin drops (postoperative value at 4 hours 33.8 ± 5.3 g.L−1 versus baseline value 42.2 ± 4.5 g.L−1). Similarly, Labgaa et al.[17] found albumin drop of 10.1 g.L−1 on postoperative day 1. There was a significant (P = 0.001) increase in CRP in the groups at 24 h after induction being more in the fentanyl group than dexmedetomidine group [Table 4]. The systemic stress response is mediated by inflammatory mediators like interleukin (IL)-6 which has a critical role synthesis of CRP, by human hepatocytes. It is a sensitive marker of inflammatory response. Wan et al.[18] found that CRP in group receiving 1 μg.kg−1 of dexmedetomidine (mean = 18.21 ± 4.52 mg.L−1) was relatively lower than control group (mean = 64.98 ± 4.75 mg.L−1). Bekker et al.[19] concluded that at postoperative day 1, mean CRP values (group control, 102.464 ± 17.027 mg.L−1; group dexmedetomidine, 85.615 ± 12.604 mg.L−1) were lower in dexmedetomidine group. In the present study, the increase in cortisol levels in Group D (mean = 41.30 ± 15.35 μg.kg−1, baseline = 21.24 ± 14.30 μg.kg−1, increase = 20.06 μg.kg−1, P < 0.001) was less as compared to fentanyl group (mean = 63.99 ± 12.31 μg.kg−1, baseline = 19.11 ± 10.78 μg.kg−1, increase = 44.88 μg.kg−1, P < 0.001) at 6 h after induction [Table 5]. Similar to our study, Yacouta et al.[20] found significantly lower value in group dexmedetomidine (mean = 15.39 ± 6.0 μg.kg−1) relative to group placebo (mean = 49.82 ± 6.81 μg.kg−1).

Table 2

Comparison of Blood glucose (mg/dL) among the groups across the time periods

Time periods	Group D (n=20)	Group F (n=20)	Group C (n=20)	P-value1	P-value2
					D vs F	D vs C	F vs C
Baseline	82.70±9.06	85.25±7.32	83.95±8.58	0.63	0.60	0.88	0.87
After incision	106.50±6.88	122.00±13.29	136.30±9.13	0.001*	0.001*	0.001*	0.001*
6 hours after induction	90.05±8.28	107.10±10.59	116.15±4.71	0.001*	0.001*	0.001*	0.003*
24 hours after induction	82.20±9.57	87.90±17.61	87.15±11.08	0.34	0.36	0.46	0.98

1ANOVA test, 2Post-hoc test, *Significant

Table 3

Comparison of serum albumin (g/L) among the groups across the time periods

Time periods	Group D (n=20)	Group F (n=20)	Group C (n=20)	P-value1	P-value2
					D vs F	D vs C	F vs C
Baseline	48.91±2.91	48.46±2.62	48.81±3.83	0.89	0.89	0.99	0.93
After incision	48.87±2.92	48.45±2.62	48.78±3.83	0.90	0.90	0.99	0.94
6 hours after induction	46.86±3.41	40.90±2.92	40.58±3.61	0.001*	0.001*	0.001*	0.95
24 hours after induction	46.77±3.42	40.82±2.96	40.86±3.73	0.001*	0.01*	0.001*	0.99

1ANOVA test, 2Post-hoc test, *Significant

Table 4

Comparison of CRP (mg/L) among the groups across the time periods

Time periods	Group D (n=20)	Group F (n=20)	Group C (n=20)	P-value1	P-value2
					D vs F	D vs C	F vs C
Baseline	16.45±5.55	17.82±5.57	15.68±5.82	0.48	0.72	0.90	0.46
After incision	16.64±5.51	17.98±5.35	15.82±5.67	0.46	0.72	0.88	0.43
6 hours after induction	16.92±5.65	18.27±5.50	16.02±5.70	0.44	0.72	0.86	0.41
24 hours after induction	20.49±5.95	29.92±5.70	31.80±7.40	0.001*	0.001*	0.001*	0.62

1ANOVA test, 2Post-hoc test, *Significant

Table 5

Comparison of serum cortisol (mcg/dL) among the groups across the time periods

Time periods	Group D (n=20)	Group F (n=20)	Group C (n=20)	P-value1	P-value2
					D vs F	D vs C	F vs C
Baseline	21.24±14.30	19.11±10.78	18.20±10.03	0.70	0.83	0.69	0.96
6 hours after induction	41.30±15.35	63.99±12.31	64.03±8.76	0.001*	0.001*	0.001*	1.00

1ANOVA test, 2Post-hoc test, *Significant

Our study was limited to only one kind of surgery, i.e., laparoscopic cholecystectomy. Furthermore, other surgical stress markers such as serum catecholamines, IL-10, and tumor necrosis factor α were not taken into consideration.

CONCLUSION

Premedication with dexmedetomidine and fentanyl has effectively modulated the neuroendocrine stress response of laparoscopic cholecystectomy under general anesthesia. The dexmedetomidine premedication was better when compared to fentanyl premedication. Modulating the stress response to surgery might enable laparoscopic cholecystectomy in obese, hypertensive, and cardiac compromised patients and may be a key factor in improving the outcome of these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.