European Journal of Cardiovascular Medicine

When it comes to safety and long-lasting post-operative pain treatment, regional anaesthesia is a great option. One of the greatest techniques in contemporary regional anesthesia is epidural blocking, which improves intraoperative haemodynamic control, relieves postoperative pain, and speeds up recovery from surgery, particularly in orthopaedic procedures. Many adjuvants, including epinephrine, neostigmine, and opioids, have been used in conjunction with local anesthetics to extend the duration of post-operative analgesia. However, these adjuvants have been linked to adverse effects, including respiratory depression, pruritus, drowsiness, nausea, and vomiting. In epidural blockade, selective alpha-2 adrenergic agonists have also been employed as an adjuvant. Clonidine hydrochloride was the first drug from the group and was found clinically useful in the perioperative period. Introduced to clinical practice in 1999, dexmedetomidine-a more potent and highly selective alpha-2 adrenoceptor agonist than clonidine-quickly gained popularity for a range of anesthesiology purposes.[1-4] Dexmedetomidine acts on the rostral ventrolateral medulla (RVLM, cardiovascular regulatory center), downregulating the neuronal activity of the RVLM, which lowers vascular resistance.

It is also highly lipid soluble, has a strong meningeal penetration, and can readily enter the spinal cord and brain after being administered by the epidural route. It takes longer for dexmedetomidine to reach the threshold concentration of binding to α2 receptors in the central nervous system because its binding to spinal cord α2 adrenoreceptors is significantly higher than that in the brain. It may even lower the concentration of dexmedetomidine entering the central nervous system, which would delay the time it takes for the epidural infusion of dexmedetomidine to act on the central system of cardiovascular regulation in the RVLM.

In order to assess and compare the haemodynamic profiles of bupivacaine alone and in conjunction with modest doses of dexmedetomidine, the current prospective study was conducted in orthopedic surgery patients.

This was a prospective randomized study carried out over a period of 18 months involving 60 patients aged 20-55 years of ASA grade I & II scheduled for elective lower limb surgeries, divided equally into two, Group D & Group P. Group D patients were administered 18 ml of 0.5% isobaric bupivacaine with 0.5 µg/kg dexmedetomidine. Group P patients were administered 18 ml of 0.5% isobaric bupivacaine with normal saline, volume made equivalent to that of dexmedetomidine. Those with a BMI ≤19 & ≥ 30.0, an international normalized ratio > 1.3, platelets < 100,000, patients on anticoagulant therapy, neurological disease, cardiac or renal insufficiency, spinal deformities, allergy or intolerance to local anesthetics, and ASA grade III and above were excluded from the study. Continuous monitoring of HR, RR, SBP, DBP, MAP, SpO₂, and ECG were done. Readings were recorded intraoperatively every 5 minutes for the first 60 minutes, then every 15 minutes till the end of surgery and thereafter every 30 minutes till the time for rescue analgesia. Heart rate less than 60 beats/min was treated with intravenous atropine 0.6 mg. SBP < 20% of baseline value or less than 90 mmHg was treated with additional Ringer's lactate solution intravenously or, if needed, injection of mephenteramine 6 mg titrated according to blood pressure. Sedation score was assessed periodically.

The SPSS (Statistical Package for the Social Sciences) for Windows software (trial version 20; SPSS Inc., Chicago) was used to analyze the data after it was imported into Microsoft Excel (Windows 10, version 2007). For continuous variables, descriptive statistics like mean and standard deviation were employed, whereas for categorical variables, they were frequencies and percentages. Data was visually represented using bar graphs. The student t-test was used to see whether the means of the two independent groups differed. The chi-square test was performed to determine whether two categorical variables were associated. A significance level of 0.05 was established.

The majority of the participants (43% and 30%) were in the age group of 41-50 years in group D and group P. This was followed by 51-60 years. 23.3% and 26.7% in group P and group D, respectively. In total, the majority (36.7%) were 41-50 years of age. There was no significant difference in age group distribution of group P and group D (P=0.653). Both the P and D groups were comparable in terms of age distribution. The mean age ± standard deviation was 42.90 ± 10.19 and 41.60 ± 11.99 in the P and D groups, respectively, and in total it was 42.25 ± 11.05. The ages of the participants in total ranged between 20 and 55 years.

Table 1: Age Distribution

The majority of the participants (70%) were males in the P and D groups. There was no significant difference in sex distribution of P and D groups (p=1.000). Both the P and D groups were comparable in terms of sex distribution.

The mean and standard deviation of height in groups P and D were 163.90±1.48 and 167.03±1.52, respectively. There was no significant difference in height of P and D groups (p=0.145). Both groups were comparable in terms of height distribution. The mean and standard deviation of weight in groups P and D were 61.77±1.63 and 64.17±1.76, respectively. There was no significant difference in the weight of the P and D groups (p=0.322). Both groups were comparable in terms of weight distribution.

The mean saturation in both groups was comparable to each other and was maintained at 99% from induction till 300 mins. There was no statistically significant difference in saturation of both groups, P and D, from induction till 300 mins later.

The mean heart rates in both groups were comparable to each other at baseline till 20 mins after induction. There was no statistically significant difference (p>0.05). From 25 mins after induction till 300 mins thereafter, the mean heart rate in group P was higher than in group D. This difference was statistically significant (p<0.05).

At baseline, the mean SBPs in the two groups were similar. The change was not statistically significant (p>0.05). Group D's mean SBP was greater than group P's from five minutes after the test dose until thirty-five minutes later. There was a statistically significant difference (p<0.05). Between 90 and 150 minutes after induction, group P's mean SBP was significantly higher than group D's (p<0.05).

At baseline, the mean DBPs in the two groups were similar. The change was not statistically significant (p>0.05). Group D's mean DBP was higher than group P's from five minutes after induction to thirty-five minutes later. There was a statistically significant difference (p<0.05). Group P's mean DBP was significantly greater than group D's from 90 minutes following introduction to 180 minutes later (P<0.05).

At baseline, both groups' mean MAPs were similar to one another. The change was not statistically significant (p>0.05). Between 5 and 35 minutes after introduction, group D's mean MAP was greater than group P's. There was a statistically significant difference (p<0.05). Between 75 and 180 minutes after induction, group P's mean MAP was significantly higher than group D's (p<0.05).

The duration of sensory and motor block and time for rescue analgesia were all greater in group D than in group P; this difference was statistically significant with p<0.001.

Figure 5: Graph of Comparison of Study Variables in Two Groups of Patients Studied

 All participants (100%) in group P had a sedation score of 1. In group D, 80% had a sedation score of 2, and the remaining 20% had a sedation score of 3. This difference was statistically significant with p<0.001.

Table 2: Sedation Score - Frequency Distribution of Patients in Two Groups Studied

30% of participants in group D and 13.3% of participants in group P had side effects. 10% of the participants in group D had bradycardia and 20% had hypotension. 10% and 3.3% in group P had hypotension and bradycardia, respectively. Overall, hypotension was the common side effect (15%) followed by bradycardia (6.7%).

There was no significant difference in age group distribution (p = 0.653), sex distribution (p = 1.000), ASA distribution (p = 1.000), height distribution (p = 0.145), & weight distribution (p = 0.322) of Group P and D. As a result, the two groups were similar. The two groups' oxygen saturation levels did not differ in a way that was statistically significant. Between 25 and 300 minutes after induction, group D's mean heart rate was lower than group P's. There was a statistically significant difference (p<0.05). The mean systolic, diastolic, and mean blood pressures were significantly lower in the D group compared to the P group at various study points.

Bhawana Rastogi et al.,^[5] conducted research to study the effect of dexmedetomidine as an adjuvant to epidural 0.75% ropivacaine in patients undergoing infraumbilical surgery using 0.6 µg/kg⁻¹ of dexmedetomidine. Patients in Group A and Group B had similar baseline heart rates of 90.88 ± 15.46 and 96.43 ± 13.76 beats/min, respectively, with no discernible intergroup differences (p=0.094). Until 60 minutes after the study drug was administered, there was no statistically significant difference in heart rate between the two groups (p<0.05). The mean heart rate difference between 75 minutes and 8 hours throughout the intraoperative period was statistically significant (p value 0.000-0.026). The two groups' preoperative mean systolic and diastolic blood pressures were similar (p=0.274). While the difference in the mean DBP of both groups from 5 to 60 minutes was found to be statistically significant (p-value 0.004-.041), the difference in the mean SBP only after 180 minutes was found to be statistically significant (p-value 0.019). These hemodynamic changes were in line with our observations.

The cardio-respiratory parameters remained stable throughout the study period, which reaffirmed the established effects of α-2 agonists in providing a hemodynamically stable perioperative and postoperative period. The decrease in heart rate caused by α-2 agonists can be explained on the basis of their central action, where they decrease the sympathetic outflow and norepinephrine release.^[6,7] The requirement of vasopressors for the maintenance of stable hemodynamic

parameters did not reveal significant differences between both the groups on statistical comparison. One of the most striking findings of our study was the absence of respiratory depression in patients who received dexmedetomidine; this finding was consistent with other research studies that found no clinically detectable respiratory depression at all in multiple human subjects.^[8-10]

Zeng, S et al.,^[11] observed that the influence on patient heart rate appeared to be greater in the epidural, ED group compared to the intravenous, VD group, recommending that epidural infusion of dexmedetomidine had a more tremendous impact on

heart rate than on blood pressure. Patients with sinus bradycardia should be carefully chosen for the epidural route to dexmedetomidine since it was believed that there was a superposition effect of the drug's infusion through various channels, altering cardiac sympathetic vagal activity.

Additionally, in the same study, the VD and ED groups' serum NE levels were lower than those of the NS group. This was thought to represent the pharmacological impact of dexmedetomidine blocking the central sympathetic nervous system, which in turn prevented peripheral NE release. Dexmedetomidine primarily lowers peripheral vascular resistance by reducing NE release, which results in dilated blood pressure reduction. This was demonstrated by the significant (P < 0.001) decrease in plasma NE concentration in the ED group compared to the VD group at 30 minutes and 1 hour after drug administration. This was consistent with the trend of blood pressure changes in the three groups mentioned above.

According to the findings of a study by Zeng S et al.,^[11] patients' perioperative haemodynamic parameters could be decreased to varied degrees by intravenous infusion or epidural dexmedetomidine when compared to the control group. The ED group provided improved haemodynamics, a lower incidence of hypotension, a shorter anaesthesia onset, a more thorough blocking, and a longer analgesia than the VD group.

Group D individuals in the Chakole et al.,^[12] study had a mean heart rate reduction of 35.2% of the preoperative mean pulse rate. The mean heart rate in groups B and C decreased by 22.1% and 29.9%, respectively, from the mean heart rate prior to surgery. When 0.6 mg of atropine was injected intraoperatively, bradycardia responded. The pulse rates of none of the individuals were 30% below the baseline. In their research, Sukhminder Jit Singh^[13] and Taylor Brandao Schnaider et al.,^[14] demonstrated a 20% to 30% decrease in pulse rate. Changes noticed in respiratory rate were not clinically significant in any group when compared with their base line preoperative respiratory rate. SpO2 stayed above 98% for the duration of the observation. The mean preoperative systolic and diastolic blood pressure in each group was between 132.4 and 139.4 and 74.3 and 79.9 mm Hg, respectively. Group B individuals experienced a maximum reduction of 19.7% in diastolic pressure and 33.1% in systolic pressure. In patients in group D, there was a decrease of 31.2%, or more than 30%, from the preoperative mean systolic pressure. Mephentermine 3- 6 mg IV bolus was well received by hypotensive patients. The blood pressure drop in groups A and C was less than 30%. In their research, Sukhminder Jit Singh et al.^[13] and Taylor Brandao Schnaider et al.,^[14] similarly noted a decrease in systolic blood pressure of over 20% when they administered 1.0 to 2.0 mcg/kg of dexmedetomidine.

A very selective α2-adrenergic receptor agonist, dexmedetomidine can decrease a variety of surgical stress reactions while preserving hemodynamic stability. Perioperative HR and SpO₂ did not significantly change between the two groups (P>0.05), according to the findings of the Kong D et al.^[15] investigation. Following anaesthesia, the observation group's MAP and VAS scores were considerably lower than the control group's (P<0.05). This is due to the fact that Dex can successfully lower blood pressure by activating the α2 receptor in the motor neuron complex in the dorsal medulla oblongata and reducing the intraoperative hypertension reaction. In addition, dexmedetomidine can suppress the release of adrenaline so that the tension of the sympathetic nervous system will be lessened, resulting in analgesic and antiemetic effects.

Sarabjit Kaur et al.,^[16] conducted a study to compare the hemodynamic, sedative, and analgesia potentiating effects of epidurally administered dexmedetomidine when combined with ropivacaine. The study concluded that epidural dexmedetomidine as an adjuvant to ropivacaine is associated with prolonged sensory and motor block, hemodynamic stability, prolonged postoperative analgesia, and reduced demand for rescue analgesics when compared to plain ropivacaine.

D Jain et al.,^[17] conducted a study to evaluate the perioperative effect of epidural dexmedetomidine in conjunction with intrathecal bupivacaine. The study concluded that the addition of 2 µg/kg dexmedetomidine epidurally to 2.5 ml of intrathecal bupivacaine prolongs the duration of analgesia and decreases the requirement of rescue analgesics in patients undergoing lower-limb orthopedic surgery, with a significant fall in pulse rate and mean arterial pressure.

However, there was no statistically significant variation in the perioperative heart rate in research by Saravia et al.,^[18] When they analyzed the epidural block features of two groups of 20 patients each, they discovered that there was no significant difference between the two groups' onset times for sensory block and the time it took to accomplish sensory block until T10 (p>0.05). The study's limited sample size (n=20) may be the cause of this discrepancy in their findings. Additionally, they discovered that the group receiving dexmedetomidine experienced analgesia for a much longer period of time than the control group, and that the group receiving dexmedetomidine had motor blockage for a significantly longer period of time—on average, 30% longer than the control group.

Dexmedetomidine's sedative action is most likely caused by activating presynaptic alpha-2 adrenoreceptors in the locus coeruleus, which inhibits norepinephrine release.^[19] In addition, inhibiting adenylate cyclase may result in a hypnotic response.^[20] The dexmedetomidine group had higher sedation scores, according to the current study. Thirty minutes after anaesthesia was administered, Saravia et al. examined the bispectral index and found that patients in the dexmedetomidine group were more sedated and had lower bispectral values than those in the control group (p<0.05).^[18]

The addition of dexmedetomidine, an alpha-2 agonist, to the local anesthetic solution for the conduct of a lumbar epidural block in the dose of 0.5 mcg/kg provides a stable hemodynamic milieu during elective lower limb surgeries with good block characteristics, improved sedation scores and enhanced postoperative analgesia.

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