A prospective, randomized, triple-blind comparative study of ropivacaine-dexmedetomidine versus ropivacaine alone in peribulbar blocks

Abstract

Background and Aims:

Bupivacaine and lidocaine mixtures are the commonly used local anesthetic drugs for the peribulbar blocks. Because of its safe anesthetic profile, ropivacaine is being investigated as an alternative agent. Several centers have evaluated the effect of the addition of an adjuvant like dexmedetomidine (DMT) to ropivacaine in enhancing the block characteristics. We proposed to evaluate the effect of the addition of DMT to ropivacaine versus a control group not having DMT as adjuvant.

Material and Methods:

A prospective, randomized comparative study was conducted on a total of 80 patients attending our hospital for cataract surgeries. Patients were allocated into four groups of 20 each (n = 20) and peribulbar blocks were given 6 mL of 0.75% ropivacaine in group R and 6 mL of 0.75% ropivacaine plus 10 μg, 15 μg, and 20 μg DMT, respectively, in groups RD1, RD2, and RD3.

Results:

When DMT was used as an adjunct to ropivacaine, there was a prolongation of the duration of the sensory block.

Conclusion:

In peribulbar blocks, 6 mL of ropivacaine 0.75% produces satisfactory block characteristics, and the addition of 10 μg, 15 μg, or 20 μg of DMT as an adjuvant to ropivacaine 0.75% had the effect of significantly prolonging the duration of the sensory block, which is directly proportional to the dose of DMT employed. However, 20 μg of DMT added as an adjuvant to ropivacaine 0.75% appears to be the optimal dose, as this anesthetic drug mixture provides maximum prolongation of the sensory block besides providing satisfactory operating conditions, acceptable sedation levels, and stable hemodynamic parameters.

Introduction

For cataract surgeries, peribulbar block is the most widely used anesthetic technique in preference to other methods.^[1] To date, different combinations of bupivacaine 0.5% and lidocaine 2% are used for these blocks with or without various adjuvants. Recently, there are published case reports of severe cardiotoxicity resulting from inadvertent intravascular injection of bupivacaine while administering the blocks.^[2] As revealed by several case reports, the use of lidocaine in peripheral nerve blocks produces hypersensitivity reactions, transient neurological symptoms, and cardiac arrhythmias.^[3] Because of the above facts, there is a trend to switch over to safer alternative anesthetic agents like levobupivacaine and ropivacaine.

Ropivacaine is structurally related to bupivacaine and is a pure S(-) enantiomer. Like bupivacaine, it causes reversible inhibition of sodium ion influx and thereby blocks the impulse conduction in the nerve fibers. It was developed to reduce the potential cardiotoxicity associated with bupivacaine.^[4] The potency of ropivacaine compared with bupivacaine is two-thirds of the sensory block and half of the motor block.^[5] Ropivacaine is used in concentrations of 0.75% and 0.5% in regional blocks and is reported to yield satisfactory sensory block but a weak motor block compared with bupivacaine.^[6] Comparison of different concentrations of ropivacaine 1.0%, 0.75%, and 0.5% had shown that the concentration of 0.75% was optimal in producing satisfactory block characteristics.^[7] Some case studies reveal that bupivacaine given for peribulbar blocks produces a burning sensation in the eye, whereas no such symptoms are reported during ropivacaine injection.^[8]

Several drugs such as DMT, clonidine, fentanyl, midazolam, and dexamethasone are used as adjuvants to local anesthetic agents to enhance their block characteristics. In this context, DMT, an alpha-2 receptor agonist was adjudged as providing satisfactory operating conditions with good analgesia and sedation and stable hemodynamic function.^[9,10] DMT produces analgesia through its peripheral actions by reducing the release of nor-epinephrine and centrally by inhibition of substance P release in the nociceptive pathways at the neurons of the dorsal root ganglion.^[11] Case studies demonstrate that DMT added as an adjuvant to the local anesthetic agents in peribulbar blocks had significantly shortened the duration of the onset of the block and also prolonged the duration of the block both motor and sensory.^[12] Based on the above findings, we hypothesized that the addition of DMT as an adjuvant to ropivacaine can result in satisfactory block characteristics. Furthermore, ropivacaine is reported to be less cardiotoxic compared with bupivacaine. Resuscitation of cardiac toxicity resulting from ropivacaine is reported to be more successful than bupivacaine-induced cardiac toxicity.^[13] Ropivacaine causes vasoconstriction of orbital vessels leading to lowering of intraocular pressure, which is considered to be useful in cataract surgeries.

Given the above facts, we undertook the present study to evaluate the onset and the duration of the peribulbar block with ropivacaine 0.75% plus DMT added as an adjuvant in different concentrations versus ropivacaine 0.75% used alone. We also wanted to find out what is the optimum dose of DMT in altering the block characteristics. Hyaluronidase 90 IU was added to the anesthetic drugs used for all the patients, as it is reported to hasten the time of onset of the block as well as enhance the quality of the block.^[14]

The primary outcome variables studied were the onset of the motor and sensory block and the total duration of the sensory block. The secondary outcome variables studied were the alterations in mean arterial pressure (MAP), pulse rate (PR), respiratory rate (RR), arterial oxygen saturation (SaO₂), Ramsay sedation score (RSS), and any adverse drug effects. The total analgesic requirement in the first 24 h after the surgery, surgeon assessment scores regarding the operating conditions, and the patient’s assessment scores about their anesthetic experience were also the other secondary outcome variables investigated.

Material and Methods

A prospective, randomized, and triple-blind comparative study was conducted on a total of 80 patients attending our hospital for cataract surgeries between March 15, 2020 and February 28, 2021. While conducting the study, we strictly observed the ethical standards of the committee on human experimentation as per the Declaration of Helsinki and obtained the approval of the Institutional Ethical committee vide its letter Rc No: IEC/14022020, dated 14/2/2020. Before enrolling the patients, we registered our study with the clinical trial registry of India vides Ref No. CTRI/2020/03/023951.

By adopting a simple random sampling by lottery method from among the 200 adult patients attending our hospital for cataract surgery, 100 were selected for our study. They were screened by applying inclusion/exclusion criteria and those who gave their consent to participate in the study numbering 80 were finally enrolled for the study. Details of the study protocol, the methodology, and all the consequent risks and benefits were explained to the participants in their mother tongue before enrolling them for the study, and written informed consent was obtained in the presence of two witnesses.

Exclusion criteria followed for our study were patients refusing the regional block, those on anticoagulant therapy, and those with a history of allergy to study drugs, mental abnormalities, those who had previous ophthalmic surgery; those having diabetes mellitus poorly controlled, and those with high myopia, glaucoma, posterior staphyloma, ocular infection, and orbital anomalies. Inclusion criteria for our study consisted of patients both male and female gender with physical status grades I and II of the American Society of Anesthesiologists (ASA) and with an age range between 40 and 80 years attending our hospital for cataract surgery during the period from March 15, 2020 to February 28, 2021.

Computer-generated random grouping software was utilized for allotting the patients to the four study groups of 20 each (n = 20); group R, group RD1, group RD2, and group RD3. A serially numbered sealed opaque envelope method was used for allocating the patients to the respective study group. Patients of group R were given 5.5 mL of ropivacaine 0.75% plus sterile normal saline 0.5 mL to make up the total volume to 6 mL and those in group RD1, RD2, and RD3 were given 10 μg, 15μg, and 20 μg DMT, respectively, combined with 5.5 mL of ropivacaine 0.75% and sterile normal saline to make up the total volume to 6 mL. Hyaluronidase 90 IU was added to anesthetic drug mixture for all the patients in the four groups.

Before taking up for surgery, all the patients were examined in the preanesthetic clinic and routine investigations were done. Drugs having sedative effects were avoided while administering the premedication. In the preoperative room, a 20-G intravenous cannula was inserted for intravenous access and vital parameters like pulse rate (PR) mean arterial pressure (MAP), and peripheral arterial oxygen saturation (SaO₂) were monitored by an electrocardiogram (ECG) monitor, noninvasive blood pressure monitor, and pulse oximeter, respectively. Peribulbar blocks were administered by an anesthesiologist who was blinded to the drugs being administered. The operating surgeon, the patients, the data entry operator, and the statistician were blinded for the drugs being administered.

Patients were asked to fix their eyeballs in the neutral gaze position and observing strict aseptic precautions, the blocks were administered with 24-G and 25-mm long needles through two transcutaneous injections (double-injection technique),^[15] i.e., through the lower eyelid in the lower temporal quadrant and the upper eyelid in the upper nasal quadrant. After a negative aspiration test for the blood to exclude an inadvertent intravascular placement of the needle, 4 mL of anesthetic agent was injected in the lower temporal quadrant and 2 mL was injected in the upper nasal quadrant. Gentle intermittent manual compression was applied on a sterile cotton pad placed on the eyeball, to facilitate the spread of the anesthetic solution.^[16]

Assessment of the loss of movement of the eyelid, loss of sensation over the conjunctiva, and the loss of movement of the eyeball (akinesia) was tested at every minute starting 1 min from the administration of the block till the time when total akinesia and analgesia of the eyeball was achieved. The primary outcome measures studied were the onset of the block both motor and sensory and the total duration of the sensory block as measured by the time elapsed from the onset of sensory block to the time when the pain of grade 3 intensity on visual analog scale 0 to 10 is reported by the patients in the postoperative period. Secondary outcome measures studied included changes in PR, MAP, a total analgesic requirement in the first 24 h, sedation levels, patient assessment scores, surgeon satisfaction scores, and other adverse events. A three-point scale was used for assessing the eyeball movements in the four directions of gaze.^[17] Anesthesia was considered adequate for taking up the patients for surgery when the loss of a sensation of the conjunctiva was associated with a total eyelid and eyeball movement score of zero.

Monitoring of PR, MAP, and SaO₂, and ECG was done at every 5-min intervals till the end of the surgery and at 15-min intervals in the postoperative period. Adverse events such as bradycardia, hypotension, bradypnea, nausea, vomiting, excessive sedation, and dryness of mouth were noted and appropriately treated. Postoperative pain was assessed using a visual analog score on a 0 to 10 scale and if the score was >3, rescue analgesia was provided with tablet diclofenac 50 mg orally and the time of giving analgesic tablet was noted for measuring the total period of the sensory block. Patient and surgeon satisfaction scores with the anesthetic technique were assessed on a three-point verbal rating score.^[18] Sedation levels attained during the period of the surgery and in the postoperative period were assessed by Ramsay’s sedation score.^[19]

A review of literature on peribulbar blocks revealed that the average duration of the onset of the motor block was 3 min with a standard deviation (SD) of 1 min. The sample size was calculated as 15 in each group taking SD as 1 with 80% power, 5% alpha error, and to detect a clinically significant difference of 1 min in the average times of the onset of the motor block between the groups. We included 20 patients in each group for better validation of the results and to compensate for any possible dropouts in the middle of the study.

Statistics: Data were expressed as means ± SD for parametric variables, and as the proportion and percentages for categorical variables. For the parametric data, the differences between the groups were analyzed using the one-way ANOVA test, and a post hoc Tukey’s HSD-b test was used for intergroup comparison. For analysis of nonparametric data and proportions, the Chi-square test was used. Statistical analysis was carried out using Microsoft Windows Excel 2007 and SPSS version 22 IBM and the P values of ≤ 0.05 were considered to be statistically significant.

Results

The details of the patients on enrolment, screening, and flow through the study stages are shown in the flow diagram [Figure 1]. As all the participants completed the study, the data of all the 80 participants were included for the statistical analysis. The demographic features like age, sex, weight, height, the right or left side of the eye operated, ASA grades, and axial length of the eyeball are comparable in all the groups as shown in the table [Table 1]. The vital parameters like PR, MAP, SpO₂, RR, and ECG are comparable in all the groups before administering the block and the fluctuations observed at the 5-min intervals during the administration of the block and in the intraoperative and the postoperative periods were comparable and within the clinically acceptable ranges in all the groups shown as line diagrams in the Figures 2 and 3.

Figure 1.

Flow diagram showing participants progress through the study phases

Table 1.

Demographic particulars of the participants

Demographic characteristics	Group R	Group RD1	Group RD2	Group RD3	P
Age (years) (means±SD)	61.2±9.2	60.4±9.3	55.9±11.4	60.5±9.4	0.33*
Sex (numbers) male/female	8/12	7/13	10/10	8/12	0.64*
Height (cm) (means±SD)	151.9±7	155.2±9.2	158.6±8.6	154.4±8.9	0.10*
Weight (kg) (means±SD)	53±12	56±11.1	58.3±9.5	59.05±11.8	0.33*
Side of the eye (numbers) Right/Left	11/9	10/10	12/8	10/10	0.81*
Axial length eyeball (cm) (means±SD)	22.8±1.1	23.1±1.1	22.7±0.7	22.9±0.9	0.49*
ASA grade (numbers) grade I/grade II	14/6	13/7	12/8	12/8	0.14*

*The result is not significant at P<0.05. SD=Standard deviation, R=Ropivacaine RD=Ropivacaine with dexmedetomidine, ASA=American Society of Anesthesiologists

Figure 2.

Mean arterial pressure changes in millimeters of mercury (mmHg)

Figure 3.

Pulse rate changes in beats per minute (bpm)

The onset of the lid akinesia, loss of sensation of the cornea, and the motor block is shown in Table 2 and the differences in the durations are not significant statistically. [Table 2]

Table 2.

Block characteristics

Block characteristics means (±SD)	Group R	Group RD1	Group RD2	Group RD3	P
Onset of sensory block (min)	1.5±0.6	1.2±0.4	1.3±0.4	1.8±1.6	0.63
Onset of motor block (min)	2.8±1.2	2.9±1.5	2.9±1.3	2.7±1.9	0.24
Onset of lid akinesia (min)	2.1±1.2	1.7±1.1	2±1.3	2.2±1.7	0.95
Sensory duration (hours)	3.7±0.7	5.6±1.5	6.4±1	7.9±1.1	0.00001*
Pairwise comparison R: RD1	3.7±0.7	5.6±1.5	.	.	0.00000*
Pairwise comparison R: RD2	3.7±0.7	.	6.4±1	.	0.00000*
Pairwise comparison R: RD3	3.7±0.7	.	.	7.9±1.1	0.00000*
Pairwise comparison RD1:RD2	.	5.6±1.5	6.4±1	.	0.10066
Pairwise comparison RD1:RD3	.	5.6±1.5	.	7.9±1.1	0.00000*
Pairwise comparison RD2:RD3	.	.	6.4±1	7.9±1.1	0.00102*

*The result is significant at P<0.05, n=20 in all the four groups. R=Ropivacaine group, RD1, RD2, and RD3 ropivacaine plus dexmedetomidine groups

The total duration of the sensory block shown in hours was 3.7 ± 0.7, 5.6 ± 1.5, 6.4 ± 1, and 7.9 ± 1.1, respectively, in groups R, RD1, RD2, and RD3 and the analysis of data within treatments by one-way analysis of variance test revealed the F-ratio value to be 46.478 and the P value < 0.00001, the result is statistically significant at P < 0.05 [Table 2]. The pair-wise comparisons within the four groups as analyzed by post hoc Tukey’s HSD-b test revealed that the increase in the duration of sensory block was directly proportional to the increase in the dose of DMT (7.9 ± 1.1 of RD3 >6.4 ± 1 of RD2 >5.6 ± 1.5 of RD1 as shown in Table 2, thereby clearly showing that the addition of DMT as an adjuvant in 10μg, 15 μg, and 20 μg doses to ropivacaine 0.75% had a statistically significant enhancement of the duration of the sensory block; the effect being greatest with 20 μg than with the lower doses.

No participant in the study groups required any supplemental injections for obtaining a satisfactory block and none of them required supplemental oxygen for maintaining satisfactory SpO₂ levels during the operation and in the postoperative period. The total analgesic requirement in the first 24 h postoperative period, differences in Ramsay sedation scores, surgeon, and patient satisfaction scores were comparable. We did not come across any complications like bradycardia, hypotension, chemosis conjunctiva, oculocardiac reflex, drug allergy, dryness of the mouth, nausea, and vomiting.

Discussion

Cataract surgery is undertaken under regional blocks as it is well suited to the elderly population of patients reporting for these surgeries with several comorbidities and because of its safe and simple nature. The safety profile of ropivacaine used in regional blocks was brought forth by several recent studies. As ropivacaine is considered a weak local anesthetic agent in comparison with bupivacaine, we decided to use an equipotent concentration of 0.75% ropivacaine. Further addition of DMT as adjuvant will enhance the quality of the block characteristics of ropivacaine. There are very few studies employing DMT as an adjuvant to ropivacaine in peribulbar blocks and the minimum effective dose of DMT is not known. Based on these clinical data, we wanted to evaluate DMT in three different doses of 10 μg, 15 μg, and 20 μg used as an adjuvant to 0.75% of ropivacaine versus a control group of ropivacaine alone. Compared with the control group, all three groups with DMT added as an adjuvant to ropivacaine had shown significant prolongation of the duration of the sensory block. Lower doses of DMT, i.e., 10 μg and15 μg produced comparable clinical effects like 20 μg but the duration of the sensory block was more with 20 μg dose and the difference was statistically significant in comparison with other doses. Despite extensive literature review, we could not come across any studies using ropivacaine and DMT combination in peribulbar blocks, hence we compared our study with other studies using DMT in combination with other local anesthetic agents like levobupivacaine, lidocaine, and bupivacaine.

Comparing ropivacaine with bupivacaine in peribulbar blocks, Jaichandran et al.^[20] concluded that the patients in their ropivacaine 0.75% group showed an earlier onset of analgesia of 1.97 min and akinesia of 2.77 min. Our findings of onset of analgesia of 1.5 ± 0.6 min and akinesia 2.1 ± 1.2 in our ropivacaine 0.75% group are in near agreement with theirs. They reported that in 97% of cases there was no requirement for supplemental injections as against 100% in our study and this difference could be due to the usage of DMT and hyaluronidase as adjuvants in our study. Channabasappa et al.^[12] evaluated the effect of adding DMT to lidocaine plus bupivacaine for peribulbar blocks in two different doses 50 μg and 25 μg and reported the onset of corneal anesthesia (sensory block) and globe akinesia (motor block) as 1.3 ± 0.5 and 8.2 ± 2.1 min, respectively, as against our findings of 1.8 ± 1.6 and 2.7 ± 1.9 min in our RD3 group. Duration of corneal anesthesia (sensory block) was reported as 109.3 ± 32.4 min by them, whereas we observed it to be 7.9 ± 1.1 h (474 ± 66 min). The faster onset of motor block and the prolonged duration of sensory block observed in our study may be due to the use of ropivacaine plus hyaluronidase in our study. Botros and Boulos^[21] used a 6 mL mixture of levobupivacaine and lidocaine with 100 μg DMT and 60 IU of hyalase, and had reported that the duration of globe anesthesia (sensory block) was 241 ± 10.87 min, whereas we observed it to be 7.9 ± 1.1 h (474 ± 66 min). The prolonged duration of sensory block observed in our study may be due to the use of ropivacaine 0.75% plus hyaluronidase 90 IU in our study.

Evaluating bupivacaine 0.5% plus hyaluronidase 50 IU/mL against 0.75% ropivacaine plus hyaluronidase 50 IU/mL in peribulbar blocks, Trivedi et al.^[22] reported the duration of the sensory block as 276.8 ± 75.4 min in their ropivacaine group and our results of 3.7 ± 0.7 h (222.45 ± 43.3 min), 5.6 ± 1.5 h (336 ± 9 min), 6.4 ± 1 h (384 ± 6 min), and 7.9 ± 1.1 h (474 ± 6 min) in our R, RD1, RD2, and RD3 groups, respectively, clearly demonstrate that addition of DMT to ropivacaine prolongs the sensory block in direct proportion to the dose of DMT used as an adjuvant. Varshney et al.^[23] comparing ropivacaine 0.75% with a 1:1 mixture of bupivacaine 0.5% and lidocaine 2%, reported onset of complete akinesia (motor block) as 15 min, whereas we observed the duration of the onset of motor block as 2.8 ± 1.2 min, 2.9 ± 1.2 min, 2.9 ± 1.3 min, and 2.7 ± 1.9 min, respectively, in our four groups. The faster onset of the block noted in our study clearly indicates the role of DMT and hyaluronidase used in our patients. Furthermore, they evaluated the quality of block at 1 min, 5 min, 10 min, and 15 min intervals after injection whereas we evaluated at every minute starting 1 min after completing the block and this could also be the reason for the wide difference in the duration of the blocks. Nagy et al.^[24] evaluated two different doses of DMT 0.25 μg/kg and 0.5 μg/kg combined with lidocaine and bupivacaine in the retrobulbar block and concluded that DMT 0.25 μg/kg had significantly increased the duration of retrobulbar blocks. The dose of DMT 10 μg, 15 μg, and 20 μg used in our study when calculated per kg body weight corresponding to 0.17 μg/kg, 0.25 μg/kg, and 0.35 μg/kg and the sensory duration of the blocks are 5.6 ± 1.5, 6.4 ± 1, and 7.9 ± 1.1 h, respectively, in the three groups. This clearly shows that there is a linear relationship between the duration of the block and the dose of DMT used in the blocks.

Evaluating the impact of two doses of DMT 15 μg and 30 μg added to local anesthetic mixture on the quality of single injection peribulbar block, EL-Shmaa et al.^[25] reported the onset of the sensory block as 2.22 ± 0.7 min and 1.86 ± 0.7 min as against our results of 1.3 ± 0.4 min and 1.8 ± 1.6 min in our study groups RD2 and RD3, respectively. Similarly, the onset of the motor block was reported as 3.33 ± 0.82 min and 3.2 ± 0.64 min, whereas our results are 2.9 ± 1.3 min and 2.7 ± 1.9 min, respectively. The faster onset of sensory as well as motor block in our study could be due to the usage of ropivacaine 0.75% by us and the dual-injection technique employed by us versus a single-injection technique used by them. Only limited studies are available using DMT as an adjuvant to ropivacaine in peribulbar blocks, further studies on these medications are warranted for throwing more light on this subject.

The limitation of our study is that the sample size was small and increasing the sample size could have enhanced the validity of our findings to a greater extent. As hyaluronidase is believed to reduce the duration of the onset of the block, it had the potential of acting as a confounding variable in our study. Furthermore, we could not measure the intraocular pressures during the block administration and in the postoperative period.

Conclusion

Based on our findings noted above, we conclude that in peribulbar blocks, 0.75% ropivacaine given in 6 mL volume with 90 IU of hyaluronidase produces satisfactory block characteristics, and the addition of 10 μg, 15 μg, or 20 μg of DMT as an adjuvant to ropivacaine 0.75% had the effect of significantly prolonging the duration of the sensory block, which is directly proportional to the dose of DMT employed. However, 20 μg of DMT added as an adjuvant to ropivacaine 0.75% appears to be the optimal dose, as this anesthetic drug mixture provides maximum prolongation of the sensory block besides providing satisfactory operating conditions, acceptable sedation levels, and stable hemodynamic parameters.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.