The Effectiveness of Intravenous Dexmedetomidine on Perioperative Hemodynamics, Analgesic Requirement, and Side Effects Profile in Patients Undergoing Laparoscopic Surgery Under General Anesthesia.

BACKGROUND: There is an upward surge in the use of laparoscopic surgeries due to various advantages when compared to open surgeries. Major advantages are, due to small incisions which are cosmetically acceptable and most of them are now daycare procedures. Problem of economic burden and hospital bed occupancy has been overcome with laparoscopic surgeries. All these advantages are not free from disadvantages, as hemodynamic changes such as hypertension; tachycardia and other surgical-related complications are commonly observed intraoperatively. Dexmedetomidine is one of the α2 agonist drugs which acts at both supraspinal and spinal level and modulate the transmission of nociceptive signals in the central nervous system. The basic effect of dexmedetomidine on the cardiovascular system is to decrease the heart rate and systemic vascular resistance with additional feature of opioid sparing effect. This drug has become an ideal adjuvant during general anesthesia, especially when stress is expected. Hence, the drug was studied in laparoscopic surgeries. AIMS AND
OBJECTIVES: (a) To study the effect of dexmedetomidine on hemodynamic parameters during perioperative period in patients undergoing laparoscopic surgery. (b) To study the postoperative sedation score and analgesic requirement. (c) To study the side effect profile of dexmedetomidine. SETTINGS AND
DESIGN: Randomized double blind controlled trial. SUBJECTS AND METHODS: After obtaining the Institutional Ethical Clearance, the study was conducted. Forty patients of American Society of Anesthesiologists Class I and II were enrolled in this randomized study. The patients were randomly divided into two groups; group normal saline (NS) and group dexmedetomidine. Patient received either NS or dexmedetomidine in group NS and group dexmedetomidine, respectively, depending upon the allocation. The infusion rate was adjusted according to; loading dose (1 μg/kg) over 10 min and maintenance dose (0.5 μg/kg/h) and perioperative hemodynamics was recorded. Routine general anesthesia was administered in all the patients with conventional technique without deviating from institutional protocols. Postoperatively, Rasmsay sedation score, time taken for request of first analgesic dose, and side effects if any were recorded. STATISTICAL ANALYSIS USED: The categorical factors are represented by the number and frequency (%) of cases. The continuous variables are represented by measures of central frequency and standard deviation. The statistical analysis was done by using unpaired t-test and Chi-square. P < 0.05 was considered statistically significant.
RESULTS: Significant hemodynamic changes are observed in NS group during laryngoscopy, intubation, during pneumoperitoneum formation, and during extubation. Hemodynamic stress response in dexmedetomidine group was significantly attenuated. Analgesic requirement during postoperative 24 h were much less in dexmedetomidine group when compared to NS group. No significant side effects were noted except for bradycardia; which was observed in two cases of dexmedetomidine group.
CONCLUSION: Dexmedetomidine infusion in the dose of 1 μg/kg body weight as bolus over 10 min and 0.5 μg/kg/h intraoperatively as maintenance dose controlled the hemodynamic stress response in patients undergoing laparoscopic surgery. Use of dexmedetomidine extends the pain free period postoperatively and thereby reducing total analgesic requirement. Thus, dexmedetomidine can be utilized as an ideal anesthetic adjuvant during laparoscopic surgeries.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Laparoscopic surgery or key hole surgeries are very popular nowadays due to various advantages such as the shorter length of stay in the hospital, lesser postoperative pain, and cosmetically appealing.[1] Recently, dexmedetomidine, a newer α2 agonist, has been introduced in Indian market. Dexmedetomidine was initially permitted to use in the Intensive Care Unit sedation, but now it is commonly used as an anesthetic adjuvant due to its distinct properties.[2] Various doses and routes of administration of dexmedetomidine have been tried successfully in anesthesia practice.[345] During laparoscopic surgeries because of pneumoperitoneum, various pathophysiological changes may occur in the patient. These changes are mainly rise in systemic and pulmonary vascular resistance, rise in heart rate, and decrease in the cardiac output. Position of the patient during the laparoscopic surgery also adds up for these pathophysiological changes further compromising the hemodynamics.[6] Certain steps in anesthesia such as laryngoscopy, intubation, and extubation also causes the stimulation of sympathetic nervous system leading to unacceptable hemodynamic changes. Various drugs such as opioids, beta blockers, and centrally acting sympatholytics have been tried to attenuate such stress response. Various studies have been conducted to know the effectiveness of dexmedetomidine in various doses for the prevention of stress-induced hemodynamic changes.[78] Dexmedetomidine has been used in routine anesthesia practice and studies have shown that there is a reduction of requirement of induction agents and opioids during perioperative period.[29] Though the clonidine is α2 agonist and has the property of sympatholytic, dexmedetomidine is more specific for α2 receptors when compared to it.[10] We therefore carried out this study with the primary aim of assessing the hemodynamic response and secondary aims of assessing sedation and analgesia requirement in first 24 h of postoperative recovery following intravenous infusion of dexmedetomidine in patients undergoing laparoscopic surgery under general anesthesia.

SUBJECTS AND METHODS

After obtaining approval by the Institutional Ethics Committee, written informed consent was taken from all forty patients who satisfied the inclusion criteria. All these patients were posted for laparoscopic surgery under general anesthesia.

Inclusion criteria

Age groups between 18 and 65 years, either sex, American Society of Anesthesiologists physical status Class I or II, posted for laparoscopic surgery under general anesthesia were included in this study.

Exclusion criteria

Patients with decreased autonomic control such as the elderly, diabetic patients, patients with cardiovascular pathology, pregnant or lactating women, patients unwilling to participate in the study were excluded from the study.

All the patients were fasted adequately, premedicated with tablet diazepam 10 mg and tablet ranitidine 150 mg on the night before surgery and on the morning of surgery. In the operation theater, patient's oxygen saturation by pulse oximetry, noninvasive blood pressure, respiratory rate, and electrocardiogram were monitored. A wide bore 18-gauge intravenous line was secured and infusion of ringer lactates at the rate 10 ml/kg/h started. Inside the operation room, the patient received injection fentanyl 1 µg/kg and injection midazolam 0.05 mg/kg, intravenously. Preparation of drug: The study drug was prepared by a senior resident who was not involved in the study. Both observer as well as patients was blinded from the study. In dexmedetomidine group;

Ampoule containing 200 mcg of dexmedetomidine was diluted with normal saline (NS) in a 50 ml syringe to achieve a final concentration of 4 mcg/ml. In saline group; 50 ml syringe was loaded with 50 ml of NS. Depending upon randomization, patients received either dexmedetomidine or NS. Infusion was set for loading dose (1 µg/kg), which was infused over 10 min using syringe pump. As soon as the loading dose is over, rate of infusion in syringe pump was adjusted to precalculated rate for maintenance dose (0.5 µg/kg/h).

Ten minutes after the administration of study drug, patients were preoxygenated with 100% oxygen for 3 min and induced with injection thiopentone 5 mg/kg intravenously. The intubation was facilitated by intravenous administration of injection succinyl choline 1.5 mg/kg. The anesthesia was maintained with oxygen, nitrous oxide 1:1 ratio, injection vecuronium (0.1 mg/kg), and sevoflurane (dial setting range between 1.5 and 2) using circle system. The patients were put on mechanically ventilator, and setting was adjusted in such a way that the end-tidal concentration of carbon dioxide was maintained between 35 and 45 mmHg. Throughout the procedure, intra-abdominal pressure was maintained between 12 and 14 mmHg. Any fall in heart rate <60/min is considered as bradycardia and treated with intravenous injection atropine 0.6 mg. Any fall in blood pressure more than 20% of baseline is considered as hypotension and initially treated with 200 ml of bolus ringer lactate fluid. If there was no improvement in blood pressure, then it was treated with injection mephentermine 6 mg intravenously.

At the end of operation, the infusion of study drug, nitrous oxide, and sevoflurane were stopped. The reversal was done with injection glycopyrrolate 0.008 mg/kg and injection neostigmine 0.05 mg/kg intravenously. Extubation was carried out once the patient met all the extubation criteria.

Monitoring of parameters, i.e., heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP) were noted at, before the start of infusion, 10 min after starting the infusion, immediately after induction, after laryngoscopy, and intubation at 1, 3, and 5 min. Data collected at the time of pneumoperitoneum, i.e., 1 min, 15 min, and 30 min and then every 15 min. After extubation, postoperatively 0, 15, 30, and 60 min, the vitals were recorded. Sedation was assessed by Ramsay sedation score (RSS) at 1, 15, 30, 60, and 120 min, postoperatively. The time to first rescue analgesic requirement and the total amount of analgesic drugs required during the first 24 h postoperatively were noted down. For rescue analgesia injection diclofenac sodium 1.5 mg/kg was intramuscularly administered when visual analogue score was more than 5. Throughout the study, patients were also observed for any adverse effects such as arrhythmias, respiratory depression.

RESULTS

There were no significant differences found between both the groups with respect to demographic parameters such as age, height, weight, and gender. The duration of anesthesia and type of surgery were comparable between both groups.

As shown in Table 1, the values for mean SBP before starting the infusion were comparable in both groups. The mean SBP in group NS did not show any significant change till laryngoscopy and intubation. The mean SBP showed significant rise at laryngoscopy, intubation, during pneumoperitoneum, and after extubation. The values returned to preoperative level by about 45 min after extubation.

Table 1

Comparison of mean systolic blood pressure

On the other hand, in group dexmedetomidine, the mean SBP significantly decreased during laryngoscopy, intubation, and during pneumoperitoneum. Even after extubation, there was a significant decrease in mean SBP. The values returned to preinfusion level after 45 min of extubation.

The values for mean DBP before starting the infusion were comparable in both the groups [Table 2]. In saline group, the mean DBP did not show any significant change till laryngoscopy and intubation. There was a significant rise in mean DBP at laryngoscopy and intubation, during pneumoperitoneum, and extubation. The values returned to preoperative level by about 45 min after extubation. On the other hand, in dexmedetomidine group, there was a significant fall in mean DBP values which were actually lesser than preinfusion values after 10 min drug infusion. The fall was significant even after laryngoscopy and tracheal intubation, during pneumoperitoneum in comparison with preinfusion values. But the mean DBP was equal to preinfusion values after extubation. There was better control of DBP in group dexmedetomidine compared to Group NS.

Table 2

Comparison of mean diastolic blood pressure

Table 3 shows the values of MAP recorded during various steps. Before starting the infusion MAP were comparable in both the groups. After starting saline infusion in group NS, it did not show any significant change till laryngoscopy and intubation. A highly significant rise in MAP is noted at laryngoscopy and intubation. Significant rise in MAP while creation of pneumoperitoneum and after extubation. The MAP values came down to preoperative level by about 30 min after extubation. On the other hand, in dexmedetomidine group, mean MAP values were significantly less than preinfusion values after 10 min of drug infusion and significantly less after laryngoscopy, tracheal intubation, pneumoperitoneum, and extubation.

Table 3

Comparison of mean arterial blood pressure

Table 4 shows the postoperative RSS in both the groups. When compared to both the groups, the maximum RSS of the three was seen in NS group, and in group dexmedetomidine, it was four. None of the patients had a RSS of five or six in either group. In group NS, 10% of patient had RSS of three at 1st min and 15th min of postextubation. In dexmedetomidine group, 15% of patient had RSS of four and 10% had RSS of four at 1st and 15th min of postextubation period, respectively. In dexmedetomidine group, 60 min after extubation around 80% of patients were having RSS of two.

Table 4

Comparison of postoperative Ramsay sedation score

The mean time for rescue analgesia in Group NS was 50 min and all patients from this group received rescue analgesia. However, in dexmedetomidine group, mean time for the need of rescue analgesia was 360 min. The cumulative analgesic dose requirement in 24 h of postoperative period was 195 mg in NS group, 90 mg in dexmedetomidine group. The adverse event like bradycardia was observed in dexmedetomidine group in two patients. There was no such incidence noticed in the NS group. In this study, incidence of dryness of mouth was 5% in both the group. There was no statistically significant dryness of mouth was observed in both the groups. There was no adverse incidence of respiratory depression; nausea and vomiting were noted in either group.

DISCUSSION

In 1947, Booker et al. studied the acute effects of abdominal pressure changes.[11] Hemodynamic changes are mainly observed in a patient who is undergoing laparoscopic surgery during intubation, pneumoperitoneum, reverse trendelenburg position, and while extubation.[12] All these changes are well tolerated in patients with normal cardiovascular function. One of the advantages of injection dexmedetomidine is that, it significantly reduces the release of catecholamine thus attenuating increase in systemic vascular resistance and heart rate. The adverse hemodynamic changes can be abolished with dexmedetomidine infusion and thus preventing complications.

Dexmedetomidine, as said before, is a highly selective α2 adrenergic agonist with sedative, anxiolytic, and analgesic, sympatholytic, and antihypertensive effects. Activation of α2 adrenergic receptors in the brain and spinal cord inhibits neuronal firing leading to hypotension, bradycardia, and sedoanalgesia. The presynaptic activation of α2 adrenergic receptors inhibits the release of norepinephrine. Effects of hemodynamics changes are mainly mediated by outflow inhibition of central sympathetic system.

The two groups under study were comparable to each other with respect to age, gender, and weight, duration of surgery, and anesthesia. The results of our study show that, in NS group, there was a significant rise in mean pulse rate, SBP, DBP, and MAP following laryngoscopy, intubation, pneumoperitoneum, and after extubation. These results are in consistent with the study conducted by authors Bhattacharjee et al., Keniya et al., and Tufanogullari et al.[5813] The suppression of the sympathoadrenal response was seen in dexmedetomidine group as it was observed in a study conducted by Scheinin et al.[9] Dexmedetomidine is a highly selective α2 adrenergic agonist. The mechanism of action is mainly on three types of α2 receptors. The α2A, α2B, and α2C receptors are found in brain and spinal cord. The resultant action of dexmedetomidine is sedation, anxiolysis, analgesia, and sympatholysis. Dexmedetomidine has been found to reduce both intraoperative and postoperative opioid requirement due to its opioid sparing effect.[1415] In our study, we observed, an increase in the time to receive first rescue analgesia in dexmedetomidine group when compared to NS group. The mean time for rescue analgesia in Group NS was 50 min and all patients received rescue analgesia. However, in dexmedetomidine group, mean time for the need of rescue analgesia was 360 min. The cumulative analgesic dose requirement in 24 h of postoperative period was 195 mg in NS group, 90 mg in dexmedetomidine group. Suggesting there was a decrease in total analgesic requirements in first 24 h postoperatively in patient receiving dexmedetomidine. Similar results are observed by Manne et al. in a study where the different doses of dexmedetomidine were compared with placebo.[6]

Stimulation of α2A and α2C receptors in which are seen in locus coeruleus causes sedation. Whereas action of dexmedetomidine on similar receptors located in spinal cord causes analgesia. Hypotension and bradycardia are mainly due to its action on α2A receptors of brain stem situated in vasomotor center.

In our study, RSS[16] was recorded once patient was taken inside and postoperatively after extubation at 1, 15, 30, 45, 60 min. The mean sedation score 1 min after patient is taken inside the operation theatre were 1.6 ± 0.5 in group NS and 1.4 ± 0.5 in dexmedetomidine group. Thus, the sedation scores were equal in both the groups. Ten minutes after the infusion of drug dexmedetomidine, the mean score in dexmedetomidine group was 2.9 ± 0.3, whereas in NS group, it was 1.9 ± 0.3; hence there was highly significant higher sedation scores in dexmedetomidine group. Immediately after extubation and during postoperative period, i.e., till 1 h, significantly higher sedation scores noted in dexmedetomidine group. We followed RSS as described in Table 5. Majority of the patients in group NS had the score of one but in group dexmedetomidine majority of the patients had score of three. And five patients had sedation score of four. The sedation caused by dexmedetomidine is mainly does dependent.[17] The dexmedetomidine has similar properties of clonidine but with more affinity toward its receptor and absence of respiratory depression.[18] Complication such as respiratory depression was not observed in any of the group. In our study, we did observe episode of bradycardia intraoperatively in two patients of dexmedetomidine group and were treated by injecting injection atropine 0.6 mg intravenously. None of the patient in the NS group had bradycardia. Possible reason for such a low incidence rate of bradycardia might be due to slow infusion of bolus.[19] Our study results are comparable to those of Bekker et al., in which the author observed no statistically significant increase in the incidence of bradycardia in dexmedetomidine group.[20] The incidence of the bradycardia is more common in young adults in whom the bolus dexmedetomidine administered rapidly.[21]

Table 5

Ramsay sedation score

The incidence of dryness of mouth was 5% in both the group. There was no statistically significant dryness of mouth was observed in both the groups. The results are in consistent with the study conducted by Parikh et al.[22] In this study, none of our patients had nausea or vomiting in either group. In a study conducted by Bakri et al. showed the incidence of nausea and vomiting significantly decreases as effectively as dexamethasone in laparoscopic cholecystectomy.[23] This decrease in incidence of nausea and vomiting is could be due to opioid sparing effect and lesser requirement of inhaled anesthetics.[2425] Other theories states that dexmedetomidine decreases noradrenergic activity by acting on α2 presynaptic inhibitory adreno-receptors in the locus coeruleus. The reduction in release of catecholamines due to inhibition of sympathetic outflow is also one of the contributing factors.[26]

CONCLUSION

Dexmedetomidine infusion in the dose of 1 mcg/kg body weight as bolus over 10 min and 0.5 µg/kg/h intraoperatively as maintenance dosecontrolled the hemodynamic stress response in patients undergoing laparoscopic surgery under general anesthesia. Dexmedetomidine increases the pain free period postoperatively, thus reducing the total analgesic requirement with minimal side effects and making it as ideal anesthetic adjuvant in laparoscopic surgeries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.