European Journal of Cardiovascular Medicine

After almost 30 years of struggle for survival, laparoscopy proved not only its right for existence but is now considered, even by the most persistent sceptics, to be the ‘gold standard’ for several surgical procedures. The advantages of smaller skin scars, reduced trauma to the patient, lesser post-operative pain and shorter duration of hospital stay have made laparoscopy the procedure of choice for most surgical interventions.

However these advantages of laparoscopic surgeries come at a price. The pneumoperitoneum (PNP) required for laparoscopy results in pathophysiological changes.¹  Pneumoperitoneum is produced by administration of carbon dioxide (CO₂) into the peritoneal cavity during laparoscopic procedures.^2,3  Both pneumoperitoneum and CO₂ cause adverse cardiovascular effects.⁴ Immediately after pneumoperitoneum plasma levels of norepinephrine, epinephrine and plasma rennin activity increase.⁵ The renin-angiotensin-aldosterone system is also activated by increasing catecholamine levels. All these changes come together to contribute to elevated arterial pressure, increase systemic and pulmonary vascular resistance and reduced cardiac output.⁶ Both mechanical and neurohumoral factors contribute to these hemodynamic changes.^7,8

Hemodynamic stability during peri-operative period is of paramount importance as there are many patients who have a compromised cardiovascular status and are on medications. The anaesthesiologist’s traditional approach to provide anaesthesia for laparoscopic procedures has been the emphasis on maintaining hemodynamic stability by avoiding hypertension, hypotension and tachycardia.

To prevent these adverse hemodynamic effects many interventions have been studied. They may be surgical interventions such as abdominal wall lift method (Laparotensors) providing gasless field for visualization, low intra-abdominal pressure techniques or use of Helium/Argon gas instead of CO₂. Anesthetic interventions to prevent such hemodynamic changes could be the use of various modes of anaesthesia such as epidural or spinal or combined epidural and general anaesthesia techniques for the procedure; or the use of various pharmacological drugs such as opioids, esmolol, sodium nitroprusside, nitroglycerine and alpha-2 adrenergic agonists. But the search for the ideal agent to control this instability in hemodynamics is still on.

Dexmedetomidine is a selective α₂ agonist with 16 times more specificity for alpha-2 receptors compared to clonidine. It has an elimination t_1/2 of 2-3 hours. Intravenous administration of Dexmedetomidine before induction attenuates sympatho-adrenal response to laryngoscopy and intubation.⁹

This study is attempted to evaluate the efficacy of dexmedetomidine in blunting the neuro-endocrine response and subsequent hemodynamic changes that occur during laparoscopic surgeries.

A prospective randomized clinical study was conducted in the Department of Anesthesiology, at Gulbarga Institute Of Medical Sciences, Kalaburagi. The study was carried out on 90 patients belonging to American Society of Anaesthesiology (ASA) classification for physical status I and II of either sex in the age range of 18 to 60 years undergoing laparoscopic procedures under general anaesthesia. They were randomized into two groups of 45 each.

Group D - Dexmedetomidine Group

Group S - Control Group

Inclusion criteria

1. Patients of age between 18 - 60 years
2. ASA Grade I & II patients
3. Type of surgery - elective laparoscopic surgeries
4. Mallampati grade I and II
5. Patients giving valid and informed consent.

Exclusion criteria

1. Patients with anticipated difficult airway
2. Oropharyngeal pathology
3. Patients on beta blockers, patients with conduction defects of the heart (heart blocks)
4. Patients with known allergy to the drug
5. Pregnant women
6. Morbidly obese (body mass index > 35 kg/m²)

PROCEDURE:-

Patients undergoing elective laparoscopic procedures, under general anaesthesia were screened for the eligibility. Patients fulfilling selection criteria were selected for the study and briefed about the nature of study and explained about anesthetic procedure in their vernacular language. A written informed consent was obtained from the patient.

A preanesthetic evaluation with detailed medical history and systemic examination was done and relevant investigations were advised and reviewed on the previous day and on the day of surgery. Patients were randomized into two groups:

• Group D patients received intravenous Dexmedetomidine Perioperatively. (Study group)
• Group S patients received intravenous normal saline 0.9% Perioperatively. (Placebo)

The study drug was provided as prefilled identical lml syringes for the loading dose and 50 ml syringes for the infusion dose containing study drugs, as per the randomization protocol, in dilutions of;

For loading dose:

1. Dexmedetomidine - 1ml (100mcg/ml)
2. Normal saline 0.9% - lml

For infusion:

1. Dexmedetomidine - 50m1 (1mcg/ml)
2. Normal saline 0.9% - 50ml

               Patients were explained about the study, but did not know which drug was used. Two intravenous lines were secured, one 20 G intravenous i.v cannula in the right hand for infusion of the study drug and another 18G i.v cannula in the left hand for intravenous fluids and drug administration.

After securing intravenous access, all patients were premedicated with inj. ranitidine 1mg/kg i.v and inj. Ondensetron 0.08mg/kg i.v, 500ml of crystalloids (Ringer Lactate) i.v was started. On arrival in the operation theater baseline monitors like ECG, Pulse-Oximeter and Non - Invasive Blood Pressure (NIBP) were attached. Baseline values of Heart rate (HR), Oxygen Saturation (SPO₂), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) were noted. All patients received inj. Midazolam 0.04mg/kg i.v and inj. Glycopyrrolate 4 micrograms/kg i.v. The study drug was started 20 minutes prior to induction. Patients belonging to group D received a loading dose of dexmedetomidine at 1mcg/kg over 10minutes, followed by maintenance infusion of dexmedetomidine at the rate of 0.4mcg/kg/hr. Patients belonging to the Group S received normal Saline 0.9% at a similar rate as dexmedetomidine infusion.

All patients received inj. Fentanyl l.5mcg/kg i.v 5minutes prior to induction of general anaesthesia. Patients were pre-oxygenated with 100% FiO₂ for 5minutes. General anaesthesia was induced with inj. Propofol 2mg/kg i.v Inj. Succinylcholine 2mg/kg i.v was administered to Facilitate intubation. All patients were intubated with appropriate size cuffed Endotracheal Tubes. End - Tidal Carbon dioxide (ETCO₂) was monitored throughout the surgery and maintained between 35-40 mm of Hg by adjusting the minute ventilation. General anaesthesia was maintained on O₂, N₂O, Isoflurane and inj. Vecuronium bromide 0.08mg/kg. The maximum concentration of Isoflurane used was 1.5% Pneumoperitoneum was created slowly, starting at 2 litre/min, using CO₂ and the Intra Abdominal Pressure (IAP) was maintained between 12-14mm of Hg. Fall in MAP of more than 20% of basal MAP was treated with iv fluids and iv ionotropes. For rise in MAP more than 20% of baseline MAP and not being maintained within this limit with an isoflurane concentration of 1.5%, an NTG infusion was started to maintain the MAP. Heart rate less than 50 beats per minute (bmp) was treated with inj. Atropine 0.6mg i.v. On completion of surgery patients neuromuscular blockade was reversed using inj. Neostigmine 0.05mg/kg and inj Glycopyrrolate 0.008mg/kg. Patients were extubated and transferred to post operative recovery room and observed for the next one hour for any evidence of complications or adverse events in the first 24 hours were assessed.

Hemodynamic Parameters including HR, SPO_2, SBP, DBP and MAP were noted at:

1. Preoperatively (Ml)
2. 10 minutes After starting the Study Drug (M2)
3. At Induction (M3)
4. During Intubation (M4)
5. Before Pneumoperitoneum (M5)
6. 10 minutes after Pneumoperitoneum (M6)
7. 20 after Pneumoperitoneum (M7)
8. 30 after Pneumoperitoneum (M8)

Every 30 minutes till the end of Pneumoperitoneum

9. At the end of Pneumoperitoneum (M9)
10. 10 minutes after reversal (N1)
11. Post operatively after 30minutes (N2)

Study Drug infusion will be stopped 5 minutes before reversal.

Statistical Analysis

Data obtained was decoded and entered into a Microsoft excel spreadsheet. The categorical data was expressed in terms of ratios and percentage; and continuous data expressed in terms of mean ± standard deviation. Data analysis was carried out using SPSS v:17 software. Students unpaired "t"/ Mann Whitney U test was used to compare quantitative variables in both groups. The categorical data was compared using chi square test. The probability value (p-value) less than 0.05 (p<0.05) was considered to be statistically significant

Our study comprised of 90 ASA I and II grading, undergoing elective laparoscopic surgeries, which were randomly divided into two groups: Group D and Group S comprising 45 patients each.

The patients belonging to Group D (dexmedetomidine) received inj, Dexmedetomidine intravenously in the perioperative period and the patients belonging to Group S (placebo) received normal saline in the perioperative period, predesigned variables were recorded and analyzed.

GROUP D, n: 45, received inj. Dexmedetomidine i.v., in the perioperative period.

GROUP S, n: 45, received normal saline 0.9%, in the perioperative period.

Table 1: Table showing the age distribution in both groups.

In group D, maximum number of patients i.e.28 (62.2%) were in the age group of 19-39 years, whereas 22 (49%) were in the age group of 40-60 years. In Group S, maximum number of patients i.e. 23 (51%) were in the age group of 40-60 years, whereas 17 (37.8%) were in the age group of 19-39 years. The mean age of all patients in group D was 37.06±11.56 years while that in group S was 37.77±11.78 (p=0.773, p>0.05). Thus both groups were statistically comparable as far as age was concerned.

The number of females in group D was 19 and in group S was 25. The number of males in group D was 26 and in group S was 20 (P: 0.2058, P>0.05), thus the both groups were comparable statistically as far as sex is concerned.

The mean weight of patients in group D was 66.15±7.05 kg where as in group S it was 66.02±6.12 kg. (P: 0.903, P>0.05), thus the both groups were statistically comparable as far as body weight is concerned.

Table 2: Table showing Distribution of patients according to ASA status in two groups.

NS - Not Significant

The number of ASA grade I patients in group D were 32 and in group S were 37.The number of ASA grade II patients in group D was 13 and in group S were 8. Both groups were comparable as far as the ASA grading was concerned as the p value is 0.2127, (p value>0.05).

Table 3: Demographic profile of both the groups.

NS - Not Significant

Table 4: Table showing types of surgeries included in the present Study.

LA- Laparoscopic Appendectomy.

LC- Laparoscopic Cholecystectomy.

LU- Laparoscopic Umbilical Hernia Repair.

NS- Not Significant.

Patients undergoing three types of laparoscopic surgeries were included in the present study- laparoscopic appendectomy, laparoscopic cholecystectomy and laparoscopic umbilical hernia repair. 22(49%) patients in group D and 23(51%) patients in the group S underwent laparoscopic appendectomy. 14(31%) patients in group D and 13(29%) patients in group S underwent Laparoscopic cholecystectomy. 9(20%) patients in group D and 9(20%) patients in group S underwent  laparoscopic umbilical hernia repair. P value was 0.7923 (p>0.05), which indicates that the three groups were comparable in terms of type of surgery the patients underwent.

Table 5: Table showing mean duration of pneumoperitoneum and duration of surgery in both the groups.

NS – (Not Significant)

The average duration of PNP in group D was 58.18±24.27 min whereas in group S it was 56.42±56.42 min with a p value of 0.903 (p>0.05). The average duration of surgery (Sx) was 88.69±25.78 min and in group S it was 88.20±22.96 min, with a p value of 0.799 (p>0.05). Thus the duration of surgery and that of PNP were not significant in both the groups, making the groups comparable with respect to duration of surgery and PNP.

Table 6: Table showing Heart Rate in both groups.

S - Significant, NS - Not Significant

Heart rate in Group S increased significantly when compared to Group D, after intubation (M4), before pneumoperitoneum (M5), 10 minutes after pneumoperitoneum (M6), 20 minutes after pneumoperitoneum (M7), 30 minutes after pneumoperitoneum (M8), at the end of pneumoperitoneum (M9), l0 minutes after reversal of neuromuscular blockade (N1) and 30 minutes postoperatively (N2) (p<0.05).

 Systolic Blood Pressure (SBP) in Group S increased significantly when compared to Group D, at induction (M3), after intubation (M4), before pneumoperitoneum (M5), l0 minutes after pneumoperitoneum (M6), 20 minutes after pneumoperitoneum (M7), 30 minutes after pneumoperitoneum (M8), at the end of pneumoperitoneum (M9), 10 minutes after reversal of neuromuscular blockade (N1) and 30 minutes postoperatively (N2) (p<0.05 ).

Graph 1: Graph showing changes in the Systolic Blood Pressure (SBP) in both the groups.

Systolic Blood Pressure (SBP) in Group S increased significantly when compared to Group D, at induction (M3), after intubation (M4), before pneumoperitoneum (M5), l0 minutes after pneumoperitoneum (M6), 20 minutes after pneumoperitoneum (M7), 30 minutes after pneumoperitoneum (M8), at the end of pneumoperitoneum (M9), 10 minutes after reversal of neuromuscular blockade (N1) and 30 minutes postoperatively (N2) (p<0.05 ).

Systolic Blood Pressure (SBP) in Group S increased significantly when compared to Group D, at induction (M3), after intubation (M4), before pneumoperitoneum (M5), l0 minutes after pneumoperitoneum (M6), 20 minutes after pneumoperitoneum (M7), 30 minutes after pneumoperitoneum (M8), at the end of pneumoperitoneum (M9), 10 minutes after reversal of neuromuscular blockade (N1) and 30 minutes postoperatively (N2) (p<0.05 ).

Graph 2: Graph showing changes in the Diastolic Blood Pressure (DBP) in both the groups.

Graph 3: Graph showing changes in the Mean Arterial Pressures (MAP) in both the groups.

Furthermore, alpha-2 adrenoreceptor agonists may offer benefits in the prophylaxis and treatment of perioperative myocardial ischemia. The alpha-2 adrenoreceptor agonists have an analgesic action at several sites of the peripheral and central nervous system. It also causes prolongation of epidurally or intrathecally administered local anaesthetics and opioids. Perioperative i.v. dexmedetomidine infusion has been used in various doses (from 0.2 to 0.8mcg/kg/hr) to attenuate hemodynamic responses in patients undergoing laparoscopic surgeries.

Tufanogullari B et al.¹⁰ used 0.2 to 0.8 mcg/kg/hr dexmedetomidine i.v. infusion. Bhattacharjee DP et al.¹¹ used perioperative i.v. dexmedetomidine in the dose of 0.2mcg/kg/hr. Ghodki PS et al.⁹ used a loading dose infusion of dexmedetomidine starting 1mcg/kg for 15 minutes and a maintenance infusion of dexmedetomidine at 0.2 mcg/kg/hr.

While Gourishankar RM et al.¹² compared two doses of perioperative dexmedetomidine infusion, 0.2mcg/kg/hr and 0.4mcg/kg/hr in patients undergoing laparoscopic surgeries. They found that dexmedetomidine provided good hemodynamic stability at these doses without adverse effects. Gourishankar RM et al.¹² in their study they concluded that a dexmedetomidine infusion of 0.4mcg/kg/hr provided better hemodynamic stability as compared to an infusion rate of 0.2mcg/kg/hr.

Therefore in our study, we used dexmedetomidine in a loading dose of 1mcg/kg over 10 minutes, before induction of general anaesthesia, followed by a maintenance infusion of dexmedetomidine at the rate of 0.4mcg/kg/hr. We studied the effects of dexmedetomidine on the stress response during laryngoscopy and endotracheal intubation, the hemodynamic response during pneumoperitoneum and intraoperative period.

In the present study 90 adult patients were randomly allocated to two groups of 45 each. Group D patients received inj. Dexmedetomidine as a loading dose of 1mcg/kg/hr iv, followed by an infusion of inj. Dexmedetomidine at the rate of 0.4mcg/kg/hr i.v. While patients of group S (placebo) received, 0.9% normal saline at a similar rate.

In the present study there was no statistically significant difference with respect to the demographic characteristic (Age, Sex, Weight and ASA grading) of both the groups.

Hemodynamic Variables:

Heart Rate:

In the present study the mean heart rate of patients before receiving premedication, which was considered as the baseline heart rate, was 82.57±12.513 beats per minute (bpm) in group D, whereas it was 82.73±13.30 bpm in group S. The mean heart rate varied from 69.42±10.52 to 85.71±l2.76 bpm in group D whereas it varied from 82.73±13.30 bpm to 101.91±13.57 bpm in group S.

Bhattacharjee DP et al.¹¹ and Gourishankar RM et al.¹² found that the heart rate significantly increased after laryngoscopy and endotracheal intubation and after creation of pneumoperitoneum. Studies by both the above authors found that perioperative inj dexmedetomidine infusion significantly reduced the heart rate after endotracheal intubation and pneumoperitoneum and remained lower throughout the period of pneumoperitoneum in comparison to placebo.

In the present study we found significant decrease in the heart rate in Group D (dexmedetomidine) after laryngoscopy and endotracheal intubation and with the onset of pneumoperitoneum and throughout the period of pneumoperitoneum in comparison to group S (placebo).

Ghodki PS et al.⁹ also found similar results in their study wherein there was a transient yet significant fall in the heart rate at the beginning of the dexmedetomidine infusion and that the heart rate was sustained for the entire duration of the infusion.

Dexmedetomidine is a centrally acting highly selective alpha-2 agonist. Activation of receptors in the brain and spinal cord level inhibits neuronal firing, leading to sympatholysis and thereby causing hypotension and bradycardia. The initial increase in arterial blood pressure is probably caused by the vasoconstrictive effects of dexmedetomidine when stimulating peripheral alpha-2 receptors. The incidence of hypotension and bradycardia may be related to the administration of a large i.v loading dose. Omitting the loading dose or not giving more than 0.4mcg/kg/hr reduces the incidence of hypotension or makes it less pronounced.¹³

In the present study 4 out of the 45 patients (9%) who received dexmedetomidine developed bradycardia (HR<50bpm), but responded well to treatment with anticholinergics (inj. Atropine sulphate 0.6 mg i.v). In several studies after IM and IV administration, in a small percentage of patients, dexmedetomidine caused profound bradycardia (<40 bpm) and occasionally sinus arrest or pause. Generally, these episodes resolved spontaneously or were readily treated without adverse outcome by anticholinergics.¹⁴

Blood Pressure changes:

In the present study the systolic blood pressure (SBP), the diastolic blood pressure (DBP) and the mean arterial pressure (MAP) in group S (placebo) were significantly higher than the baseline values during laryngoscopy, endotracheal intubation and throughout the period of pneumoperitoneum. Whereas in group D (dexmedetomidine) these values showed minimal variability from the baseline values during intubation and during the period of pneumoperitoneum.

In group D there was a significant fall in the MAP values before induction, before pneumoperitoneum and after release of pneumoperitoneum. There was slight increase in values (<5%) after intubation, 15 and 30 minutes after pneumoperitoneum and after extubation. The values were significantly higher at all points of time in group S.

Upon statistical comparison of the two groups, there was a significant difference in values of both the groups (for SBP, DBP and MAP) at all points of time except before premedication where the values were comparable. There was a significant fall in the SBP, DBP and MAP in patients of group D before induction. It confirmed that 10 minutes is adequate for i.v. loading dose of dexmedetomidine to act.

Ghodki PS et al.⁹ in their study confirmed that after the loading dose of dexmedetomidine infusion there was a significant fall in the SBP. After which minimal change was observed for the entire duration of pneumoperitoneum.

Bhattacharjee DP et al.¹¹ found that the MAP was significantly lower in the patients receiving dexmedetomidine infusion, in comparison to the placebo group, after induction, after intubation and pneumoperitoneum; and remained lower throughout the pneumoperitoneum and in the post-operative period.

Gourishankar RM et al.¹² when comparing two doses of dexmedetomidine infusion found that the MAP decreased significantly in the Dex 0.2 group and highly significantly in the dex 0.4 group below the pre-infusion levels. The increase in the MAP was significantly lower after intubation and extubation in the dex 0.2 group compared to the placebo group. MAP in the dex 0.4 group remained below pre-infusion levels after intubation and extubation, which is similar to the present study. Pneumoperitoneum did not produce a significant effect in both the dex groups.

Tufanogullari et al.¹⁰ compared three infusion doses of Dexmedetomidine 0.2, 0.4 and 0.8mcg/kg/hr with saline in morbidly obese patients undergoing Laparoscopic Bariatric surgery. Although the intraoperative hemodynamic values were similar in the four groups, MAP values were significantly reduced in the Dex 0.2, 0.4, and 0.8 groups compared with the control group on admission to the postanesthesia care unit (PACU). In our study also, the mean arterial pressure in Dexmedetomidine group was significantly less in PACU.

In spite of maintaining normocapnia, keeping intra-abdominal pressure below 14 mmHg and providing good potent analgesia with fentanyl, there was a significant rise in heart rate, systolic, diastolic, and mean arterial pressure from baseline in group S at all points during surgery.

In the present study effects of CO₂ pneumoperitoneum on hemodynamics and the efficacy of intravenous dexmedetomidine infusion to prevent the same were assessed. The conclusions drawn from the study are:

CO₂ pneumoperitoneum causes activation of the sympathetic autonomic nervous system leading to hemodynamic perturbations.

Perioperative intravenous dexmedetomidine as a loading dose of 1mcg/kg/hr over 10mins prior to induction, followed by an infusion of 0.4mcg/kg/hr in ASA I and II patients was found to be effective in providing intraoperative hemodynamic stability during laparoscopic surgeries without any significant adverse effects.

In addition, dexmedetomidine also blunted the stress responses to laryngoscopy & endotracheal intubation and extubation.

The intraoperative requirement of NTG was decreased by administration of i.v. dexmedetomidine.

Hence dexmedetomidine can be safely used to attenuate the hemodynamic responses during laparoscopic surgeries with the added advantage of it being an adjuvant to general anaesthesia. However additional studies are necessary to ascertain the efficacy and safety of dexmedetomidine in elderly and ASA III and IV patients, particularly in those with compromised cardiovascular function.

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