Abstract

Background

Dexmedetomidine is a potent α₂ agonist which has been used for blunting the stress responses during critical events such as laryngoscopy, endotracheal intubation, pneumoperitoneum creation, and extubation. The purpose of this study was to see the efficacy of intravenously administered dexmedetomidine at a dose of 0.5 mcg/kg in attenuating the hemodynamic responses due to pneumoperitoneum during laparoscopic cholecystectomy under general anesthesia.

Methods

Sixty patients, ASA-PS class I (American Society of Anesthesiologist physical status class I), aged between 18 and 60 years, of either sex with weight ranging from 50 to 80 kg, scheduled for laparoscopic cholecystectomy were randomized into two groups (groups A and B) in a double-blinded fashion. Both groups were pre-medicated with an injection glycopyrrolate. Group A received 100 mL normal saline (NS) over 10 minutes while group B received dexmedetomidine 0.5 mcg/kg diluted in 100 mL NS over 10 minutes before induction of general anesthesia. Heart rate, systolic, diastolic, and mean arterial pressures were noted.

Results

Following pneumoperitoneum, there was no statistically significant difference in the hemodynamic parameters between the two groups (P > 0.05).

Conclusion

Administration of dexmedetomidine at a dose of 0.5 mcg/kg before induction did not blunt the hemodynamic responses to pneumoperitoneum during laparoscopic cholecystectomy.

Keywords

dexmedetomidine, hemodynamic response, laparoscopic cholecystectomy, pneumoperitoneum

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Introduction

Laparoscopic cholecystectomy is the most common laparoscopic procedure performed and has become the standard technique of choice for cholecystectomy. Insufflation of the abdomen with the gas provides adequate visualization of the operative field. However, variations in patient positioning, physiological effects of intraperitoneal carbon dioxide (CO₂) insufflation with an increase in intra-abdominal pressure (IAP) and hypercarbia due to systemic absorption of CO₂ gas can have a major impact on cardio-respiratory functions mainly in elderly and patients with comorbidities.¹

Pneumoperitoneum creation with CO₂ gas is associated with significant hemodynamic changes which may have a negative impact on the patient’s outcome. The increase in IAP leads to an increase in systemic vascular resistance due to mechanical compression of the abdominal aorta and the production of neuro-humoral factors.² There is an increase in the release of norepinephrine, epinephrine, cortisol, vasopressin, atrial natriuretic peptide, renin, and aldosterone levels which leads to an increase in arterial blood pressure, systemic as well as pulmonary vascular resistance after the beginning of intra-abdominal insufflation.³ Pre-existing essential hypertension, ischemic heart disease, and increased intracranial pressure or intraocular pressure can be the risk factors for adverse cardiovascular events in patients with severe increases in arterial pressure.⁴

Various pharmacological agents like α₂ adrenergic agonists⁵, beta-blockers⁶, and opioids⁷ are often used to attenuate circulatory response due to pneumoperitoneum creation.

Dexmedetomidine, a pharmacologically active dextro-isomer of medetomidine, is a highly selective potent α₂ receptor agonist (α₂:α₁ = 1,620:1).⁸ It is chemically (S)-4-[1-(2, 3-dimethylphenyl) ethyl]-3H-imidazole with a molecular weight of 236.⁹ It is used for sedation, analgesia, anxiolysis, and perioperative sympatholysis. It produces its clinical actions after binding to G-protein coupled α₂ adrenergic receptors and causes hyperpolarization of noradrenergic neurons leading to suppression of neuronal firing on locus coeruleus and hence decreases noradrenaline release resulting in attenuation of sympathetic responses.⁸

Its distribution half-life is 5 minutes and elimination half-life is 2 hours. Context-sensitive half-life ranges from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion. It undergoes almost complete biotransformation through N-glucuronidation and cytochrome P450- mediated hydroxylation to inactive metabolites. Metabolites are excreted in urine (about 95%) and in feces (4%).⁸

Dexmedetomidine has been found to attenuate hemodynamic responses to intubation as well as extubation. Studies have been done previously to study the efficacy of the drug, either a single bolus dose before induction of general anesthesia or as an infusion in attenuating the stress response to pneumoperitoneum creation.^10-14 Higher dose of dexmedetomidine (1 mcg/kg) effectively blunts stress response to pneumoperitoneum.¹² Lower dose of dexmedetomidine (0.2 mcg/kg/hr) given as infusion has shown to be less effective in attenuating stress response to pneumoperitoneum.¹⁰ However, studies with a single dose of dexmedetomidine at the dose of 0.5 mcg/kg in attenuating hemodynamic response to pneumoperitoneum creation are sparse at this time of writing. This study will help to evaluate the efficacy of intravenously administered dexmedetomidine (bolus dose of 0.5 mcg/kg within 10 mins) in attenuating the hemodynamic responses due to pneumoperitoneum creation during laparoscopic cholecystectomy.

Methods

After we obtained ethical clearance from the Institutional Review Committee of Kathmandu Medical College Teaching Hospital (Ref. No 151220171) and informed written consent from the patients, 65 patients American Society of Anesthesiologists Physical Status (ASA-PS) class I and II of either sex, aged 18–60 years, weighing 50–80 kg, undergoing routine laparoscopic cholecystectomy under general anesthesia were randomly selected for this study. Patients posted for emergency surgery, patients with cardiovascular, respiratory or renal disorders, diabetes, hypertension, pregnancy, lactating, baseline bradycardia, and patients under medications such as beta blockers or clonidine, anticipated difficult intubation, more than one attempt of laryngoscopy during intubation, laparoscopic surgery turned open were excluded from the study.

The study was conducted for the duration of eight months from July 30, 2018 A.D. to March 5, 2019 A.D.

Pre-anesthetic evaluation of the patients was done a day prior to the surgery. They had been kept NPO (nil per oral) for 6 hours for solid food and 2 hours for clear fluid. Premedication with tab ranitidine 150 mg and tab metoclopramide 10 mg orally at night before surgery and in the morning on the day of surgery was done.

All the patients were double-blinded and randomly assigned into either of the two groups based on the computer-generated random allocation list which was made available only to an anesthesiologist not involved in the study and data collection. The control group (group normal saline [NS]) received 100 mL NS while the dexmedetomidine group (group Dexmed) received dexmedetomidine 0.5 mcg/kg in 100 mL NS.

In the operating room, a non-invasive blood pressure cuff, electrocardiogram, and pulse oximeter probe were attached. Baseline vitals (heart rate [HR], systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP], and saturation of oxygen [SpO₂]) were noted. The HR and SpO₂ were continuously monitored throughout the intraoperative period. SBP, DBP, and MAP were measured every 5 minutes and noted as per the defined time points of the study.

The patients were premedicated with an injection glycopyrrolate 0.2 mg irrespective of the group assigned. Before induction, the total volume of the study drug according to the group allocated was diluted in 100 mL NS. Dexmedetomidine available at 100 mcg/mL was diluted in 10 mL NS resulting in a final concentration of 10 mcg/mL. According to the group allocated, the study drug based on the weight of the patient was diluted in 100 mL NS and administered over a period of 10 minutes with the use of an infusion pump. The preparation of the study drug was performed by an anesthesiology assistant who was not involved in the study and handed it to an assessor. The study drug was administered by the assessor. Decoding of blinding to the assessor was done only at the time of tabulation and result analysis.

All the patients were induced with an injection propofol 2.0 mg/kg, analgesia was provided with an injection fentanyl 1.0 mcg/kg, and muscle relaxation was achieved with an injection rocuronium 1.0 mg/kg. The patients were intubated with appropriate size endotracheal tubes after one minute of muscle relaxant administration. After tracheal intubation, mechanical ventilation was performed with a tidal volume of 5–6 mL/kg and the respiratory rate was adjusted to maintain an end-tidal carbon dioxide (EtCO₂) of 30–35 mmHg. The maintenance of anesthesia was done with isoflurane (1.0–2.0 volume %) which was titrated as per the blood pressure and HR reading. Muscle relaxation was maintained with an injection rocuronium (0.1 mg/kg) as per requirement which was assessed by the appearance of “curare cleft” in the capnograph or eliciting spontaneous respiratory efforts in the reservoir bag. Injection paracetamol 1.0 gm was administered to supplement analgesia after induction.

The CO₂ gas was insufflated at the rate 3–5 L/min maintaining the IAP of 12–15 mmHg. The same CO₂ insufflator (Stryker, Kalamazoo, MI, USA) was used in all the patients. The operating table was placed in reverse trendelenburg position (30° head up) and 20° left tilt during the surgery in all the patients.

During the surgery, Ringer’s lactate solution was administered at 15 mL/kg/hr. The total amount of fluid administered was noted.

HR and non-invasive blood pressures were noted and compared at the following time points: Baseline—before infusion of the study drug (B), before induction of anesthesia (I0), 3 minutes after intubation (I3), before pneumoperitoneum creation (P0), 10 minutes after pneumoperitoneum creation (P10), 20 minutes after pneumoperitoneum creation (P20), 30 minutes after pneumoperitoneum creation (P30), 5 minutes after the release of CO₂ (R5), and 5 minutes after extubation (E5).

Intraoperative hypotension (fall in MAP by 20% of the baseline value) was treated by decreasing the concentration of isoflurane, administering intravenous fluid bolus, and if required injection mephentermine 6.0 mg was given in repeated doses. Hypertension (rise in MAP of over 20% of the baseline value) was managed by increasing the concentration of isoflurane (up to 2.0 volume %). Blood pressure of > 160/100 mmHg was treated by administering injection esmolol 0.5 mg/kg bolus over 30 seconds. Tachycardia (HR > 100 beats per minute) was managed by increasing the depth of anesthesia by increasing the concentration of isoflurane (up to 2.0 volume %) and if not well controlled, analgesics were added, initially injection ketorolac 30 mg followed by injection fentanyl 0.5 mcg/kg if required. Bradycardia (HR < 50 beats per minute) was treated by administering injection atropine 0.6 mg.

Injection ondansetron 0.1 mg/kg was given at the end of surgery. The neuromuscular blockade was reversed with an injection of neostigmine 0.05 mg/kg and glycopyrrolate 0.007 mg/kg after spontaneous respirations were achieved. The patients were extubated once the respiratory efforts were adequate and shifted to the postoperative ward after fully awake.

Statistical Tool

Sample Size

Sample size of the study was calculated based on the following formula, n = 2 [(Zα + Zβ)² × σ²] / e² where n = sample size,

Zα = Z score at α, Zβ = Z score at β, σ = standard deviation, e = allowable error, σ = (10.10 + 8.79) / 2 = 9.45 (mean of standard deviation between MAP between two groups)¹⁰, e = 5

Therefore, N = 2 × (1.96 + 0.845)² × (9.45)² / (5)² = 56.2. To increase the power, 30 patients were included in each group with a total sample size of 60 patients.

Statistical analysis was performed using SPSS version 20 (IBM Corp., Armonk, NY, USA). Data were expressed as mean and standard deviation. Age, weight, body mass index (BMI), and perioperative variables were analyzed using an independent sample t-test. Categorical data such as gender, intraoperative adverse events, and analgesic requirements were analyzed by Chi-square test. Hemodynamic parameters such as HR, SBP, DBP, and MAP were expressed as mean and standard deviation. Comparison between the groups was done using an independent sample t-test after homogeneity of variance was present as assessed by Levene’s test for equality of variances. If homogeneity was not present, Mann-Whitney U was performed instead. A P-value of < 0.05 was considered statistically significant.

Results

Out of 65 consented patients, 60 patients were included and analyzed in this study. In other words, 5 patients were excluded intraoperatively as 3 patients were turned open and 2 patients had more than one attempt at intubation as shown in Figure 1. The excluded patients were replaced serially according to the number and group they were assigned. In this study, 60 patients with 30 patients in each group were included. All the patients belonged to ASA-PS class I.

As shown in Table 1, both the study groups were comparable to each other with respect to age, sex, weight, BMI, NPO hours before surgery, total intravenous fluid received, total duration of surgery, total anesthetic time, total awakening time, and IAP after pneumoperitoneum creation (P > 0.05).

Baseline HR was not significant between the two groups (P > 0.05) as the mean HR of group NS was 84.23 ± 14.90 beats per minute while in group Dexmed it was 78.53 ± 13.81 beats per minute. In group NS, there was a significant increase in HR at all defined time points when we compared it with the baseline. Similarly, there was a significant increase in HR at all the defined time points (except before induction) after dexmedetomidine infusion when we compared it with the baseline. When we compared the groups, there was no significant difference in HR after administration of the drug at all defined time points as shown in Table 2.

As shown in Tables 3–5, the baselines SBP, DBP, and MAP of group NS was 128.30 ± 12.25, 80.7 ± 7.73, and 97.10 ± 10.70 mmHg while in group Dexmed it was 125.27 ± 13.4, 78.27 ± 10.43, and 96.47 ± 13.9 mmHg which was not significant between two groups (P > 0.05). There was no significant difference in SBP, DBP, and MAP after administration of the drug at all defined time points.

Only one patient developed bradycardia requiring treatment with injection atropine in the Dexmed group which was statistically non-significant.

For Figures 2–5, we compared the changes in HR, SBP, DBP, and MAP at defined time points in both groups (Group A—NS and Group B—Dexmed).

Discussion

Among the patients enrolled in the study, 80% of them were female which showed the high prevalence of female patients undergoing laparoscopic cholecystectomy in our hospital. Although both ASA I and II were planned to be included in the study, all the patients enrolled were ASA-PS I as most ASA-PS II patients who met the exclusion criteria were either hypertensive or diabetic.

This study showed that dexmedetomidine in the dose of 0.5 mcg/kg infusion given over 10 minutes before induction in patients undergoing laparoscopic cholecystectomy under general anesthesia was not effective in attenuating hemodynamic response caused by pneumoperitoneum creation. There were no significant changes in the HR, SBP, DBP, and MAP between the groups. However, these parameters in the Dexmed group were in a lower range compared to the control group.

During general anesthesia, intubation, pneumoperitoneum creation, and extubation are stressors to the patients which cause sympathetic responses releasing stress hormones leading to an increase in HR and blood pressure. This stress response can adversely affect the patients and cause complications such as myocardial ischemia, arrhythmia, and cerebrovascular injury in high-risk groups.¹¹ Intravenous dexmedetomidine given intraoperatively can attenuate this stress response by inhibiting the release of stress hormones such as epinephrine and norepinephrine by acting in the medullary vasomotor center.¹⁵

A study done by Hazra et al.¹² showed that intravenous dexmedetomidine or clonidine at 1 mcg/kg given 15 minutes before induction of anesthesia effectively attenuated hemodynamic response to pneumoperitoneum, dexmedetomidine being more effective.

Manne et al.¹⁰ concluded that continuous infusion of dexmedetomidine at 0.4 mcg/kg/hr started 15 minutes before induction to the end of the surgery could decrease the hemodynamic stress response to intubation, pneumoperitoneum, and extubation.

However, a study done by Parmar and Awasya¹³ showed that a single bolus dose of dexmedetomidine at a dose of 0.5 mcg/kg given over 10 minutes before induction was less effective in blunting the stress response compared to 0.75 mcg/kg.

Also, a study done by Ye et al.¹⁴ showed that intravenous infusion dexmedetomidine 0.4 μg/kg before induction could not effectively inhibit the stress response, but dexmedetomidine 0.6 μg/kg and 0.8 μg/kg could effectively restrain the intubation reaction, attenuate the intraoperative stress response, and maintain the hemodynamic stability.

In this study, though the hemodynamic parameters in the Dexmed group were in a lower range compared to the control group, it could not effectively attenuate the stress response to pneumoperitoneum. This may be due to the lower concentration of the drug used.

Cardiovascular depression leading to hypotension and bradycardia could occur following dexmedetomidine administration.⁸ This is due to its action on α₂ adrenoceptors in ventrolateral medulla and nucleus tractus solitarius. In this study, the incidence of bradycardia in the Dexmed group was low (3.33%) which might be due to the low dose and slow infusion of the drug.

Regarding the limitations of the study, only ASA-PS I patients were analyzed in the study. Low dose of dexmedetomidine (0.5 mcg/kg) was used in this study which might have led to the ineffectiveness of the drug in blunting the hemodynamic response.

Conclusion

Administration of injection dexmedetomidine at the dose of 0.5 mcg/kg 10 minutes before induction of general anesthesia in patients undergoing laparoscopic cholecystectomy did not effectively blunt the hemodynamic stress response to pneumoperitoneum.

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References