Abstract

Background

We explored the analgesic efficacy of two non-opioid adjuvants (midazolam and dexmedetomidine) with ropivacaine in children undergoing infraumbilical surgeries.

Methods

In this parallel group randomized controlled trial, 135 children aged between 2 and 8 years were recruited. Children were randomly allocated to one of three groups: RD received 1 mL/kg of ropivacaine (0.2%) with dexmedetomidine 1 μg/kg, RM received 1 mL/kg of ropivacaine (0.2%) with midazolam 30 µg/kg, and R received 1 mL/kg of ropivacaine (0.2%) with 1 mL normal saline. The primary outcome of the present study was to determine the duration of postoperative analgesia. Secondary outcomes were assessing postoperative face, leg, activity, cry, consolability (FLACC) pain score, rescue analgesics, hemodynamics, sedation scores, and adverse effects.

Results

The analgesia duration was significantly prolonged in the RD and RM group (600.0 [480.0–720.0] minutes and 600.0 [480.0–720.0] minutes, respectively) compared to the R group 360.0 (300.0–480.0) minutes (P < 0.001). The FLACC score was comparatively higher in the R group compared to the RD and RM groups postoperatively. Time for the first rescue analgesia was more prolonged in RD and RM groups when compared with the R group. Postoperative sedation was higher in the RM group up to 120 minutes postoperatively compared to the RD and R groups.

Conclusion

The combination of dexmedetomidine or midazolam with local anesthetics significantly increases the analgesia duration while minimizing adverse effects.

Keywords

analgesia, caudal block, children, dexmedetomidine, midazolam, ropivacaine

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Introduction

Regional anesthesia in children is gaining popularity over the past few decades as it reduces the usage of systemic drugs and provides better hemodynamic stability in the perioperative period and early ambulation.¹ Caudal block is a commonly used regional method of providing analgesia in children. It is a common anesthetic technique that is easy to perform with a high success rate and minimal complications.²

The main drawback of a single-shot caudal block is its brief analgesic duration. Epidural catheter placement through caudal space is not popularly practiced for fear of infections due to fecal soiling. Extended analgesia following a single caudal block can be achieved by adding an adjuvant along with local anesthetics. Various adjuvants like opioids, ketamine, dexamethasone, nalbuphine, tramadol, neostigmine, magnesium, and alpha-2 agonists have been used commonly in the caudal block.³

Opioids were commonly used adjuvants to prolong the analgesic effects. Unfortunately, several side effects have been reported associated with caudal opioids. These are nausea, vomiting, pruritis, urinary retention, and hypoventilation.⁴ Respiratory depression may occur due to the rostral spread of opioids, leading to depression in the medullary respiratory center.⁵ In caudal opioids, either alone or in conjunction with local anesthetics, the patient should be monitored at least 24 hours after surgery as the period during which the child is at risk of hypoventilation is unknown.⁶ The quest for the optimal medication combination for caudal anesthesia is ongoing.

Dexmedetomidine is a selective alpha-2 receptor agonist. It has analgesic and anxiolytic characteristics with minor adverse effects. Numerous mechanisms for intravenous (IV) dexmedetomidine-induced analgesia have been suggested; its stimulation in the central nervous system reduces calcium influx into nerve terminals, followed by inhibition of neurotransmitter release, thus promoting analgesia.⁷ It has antinociceptive effects by directly inhibiting spinal cord nociceptive neurons. Moreover, it inhibits neurotransmission in the peripheral nervous system’s sensory A-delta and C fibers. In comparison to other adjuvants, it maintains perioperative hemodynamic stability. It has sympatholytic, analgesic, and sedative action with minimal side effects like manageable hypotension and bradycardia when administered intravenously or via the caudal route.⁸

Midazolam is a benzodiazepine that has anxiolytic, sedative, and anticonvulsant effects. Its analgesic effects are mediated by gamma-aminobutyric acid-benzodiazepine receptors in the spinal cord.⁹ As an adjunct in the caudal block, midazolam is believed to extend the duration of analgesia.¹⁰

There is a paucity of literature comparing analgesia, sedation, and side effects of these two non-opioid adjuvants (midazolam and dexmedetomidine) with ropivacaine in the caudal block.¹¹ As a result, we would want to examine the use of these adjuvants in conjunction with caudal ropivacaine for children undergoing infraumbilical surgeries.

Methods

Study Settings

This trial was registered with the Clinical
Trials Registry of India (CTRI number: CTRI/
2019/08/021002) (http://ctri.nic.in/Clinicaltrials/rmaindet.php?trialid=35687&EncHid=38128.2485&modid=1&compid=1), after receiving clearance from the Institutional Ethics Committee (no. IEC/2019-20/819).

Patients

Patients aged 2–8 years scheduled for infra-umbilical surgeries under general anesthesia were enrolled in this randomized controlled trial from September 1, 2019. This study was conducted between September 1, 2019, and April 30, 2021. We excluded patients who had any of these conditions—local site infections, allergy to local anesthetics, coagulation disorders, history of neurological or spinal disorders, mental retardation, or neuromuscular problems.

Interventions

Informed written approval was taken from the parents or legal guardians and assent from the children. All the procedures were conducted in accordance with the Helsinki Declaration 2013. Once enrolled, children were randomly assigned to one of three groups using the computer randomization tool (www.randomizer.org). The allocation ratio was 1:1:1, and to conceal participants’ identity, the group recognition slip was placed in a prenumbered, packed, and dark-colored envelope. Group R: patients received (0.2%) ropivacaine (Ropizuva, 2 mg/mL, Abbott India Ltd, Mumbai, Maharashtra, India) 1.0 mL/kg + normal saline (NS) 1 mL. Group RD: patients received 1 mL/kg of ropivacaine (0.2%) with 1 μg/kg of dexmedetomidine (Dextomid, 100 μg/mL, Neon Lab. Ltd, Mumbai, Maharashtra, India) taken in 1 mL tuberculin syringe (scaled in 0.01 increments with prominent marks at zero and every 0.05 mL, e.g., 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, and so on up to 1 mL) and diluted in 1 mL NS; Group RM: patients received (0.2%) ropivacaine 1.0 mL/kg + 30 μg/kg of midazolam (preservative-free, Mezolam, 5 mg/mL, Neon Lab. Ltd) diluted in 1 mL NS.

An electrocardiogram, a pulse oximeter, and non-invasive blood pressure were connected within the operating room, and baseline values were recorded. IV access was secured if not already in place. In order to establish general anesthesia, sevoflurane was inhaled, and the correct size laryngeal mask airways were used to secure the airway. Sevoflurane at a concentration of 1%–2% was used to maintain anesthesia, along with oxygen and air. Children were positioned in the lateral position after anesthetic induction. The child’s back was cleaned with an antiseptic solution before being draped. Under aseptic conditions, the sacral hiatus was identified. A 23 G needle was inserted cephalad at a 45° angle until the sacrococcygeal ligament was pierced with a pop. After that, the needle was flattened and progressed into the sacral hiatus. In order to find the caudal space, we used the loss of resistance method. An anesthesiologist (RV) who was unaware of the medicine, administered a single-shot caudal block using the blind method, and she was not involved in the patients’ further follow-up. Another anesthesiologist, who was not involved in the research, loaded the drug. According to the allotted group, the patient received the medication in the caudal space. The drugs were delivered after negative blood and cerebrospinal fluid aspiration. The injection site was dressed, and the patient was positioned supine. Intraoperatively, no further analgesics, sedatives, or narcotics were given.

The surgical incision was made 15 minutes after the caudal block was administered. Hemodynamic stability was used to determine analgesic adequacy during surgery. Appropriate analgesia was characterized by a lack of a 15% rise in either heart rate (HR) or mean blood pressure (MBP) over baseline values immediately after the surgical incision. Analgesia failure was established as a rise in HR or MBP of greater than 15% over initial readings after 15 minutes of surgical incision. Inadequate analgesia was described as a rise in the HR or MBP 45 minutes after surgical incision. As a part of the initial protocol, it was planned that if a patient failed to have adequate analgesia induced by the caudal block, he would receive 1–2 µg/kg fentanyl intravenously, and these patients would be excluded from the study.

At the completion of the operation, the child was extubated, and the duration of anesthesia in each group was documented. The duration of anesthesia was determined as the interval between induction and extubation.

Data Collection

The patients were continuously observed for 1,440 minutes after surgery. The postoperative evaluation in the postanesthetic care unit and the ward was done by another anesthesiologist (AMM) blinded to the research groups. The face, leg, activity, cry, consolability (FLACC) scale was used to evaluate pain at 0, 60, 120, 360, 720, and 1,440 minutes after the surgery. The analgesia duration was determined by the interval between the caudal administration of the medication and the occurrence of the first FLACC score of ≥ 4.

The postoperative pain score was used to determine the requirement for rescue analgesics. Rescue analgesia was administered when patients had a pain score of more than 4 at least two times or had obvious pain symptoms. IV paracetamol was administered as a rescue analgesic at a dosage of 15 mg/kg.

The initial and subsequent use of rescue medication was recorded. The HR and MBP were monitored at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the surgery. The Ramsay sedation score (RSS) was noted at 0, 60, 120, 240, 480, and 720 minutes following the operation.

Patients were observed for any adverse events throughout the postoperative period. Respiratory depression was defined as an oxygen saturation level below 92%, necessitating supplemental oxygen. Hypotension was described as systolic blood pressure below 70 mmHg, and bradycardia as a HR below 60 beats per minute.

Outcomes Measures

The primary outcome of the present study was to determine the postoperative analgesia duration when dexmedetomidine and midazolam were administered in combination with ropivacaine in the caudal block. Secondary outcomes were assessing postoperative rescue analgesics, pain score, intraoperative and postoperative hemodynamic profile, postoperative sedation scores, and any adverse effects.

Sample Size Calculation

We could not find studies comparing midazolam and dexmedetomidine as adjuncts to ropivacaine in the caudal block. Sridhar et al.¹² conducted a multi-arm trial comparing dexmedetomidine and dexamethasone with the control group as an adjunct to ropivacaine for caudal block. They found the mean ±
standard deviation (SD) analgesia duration to be 406.25 ± 45.49, 450.00 ± 72.60, and 285.94 ± 52.78 minutes in the dexmedetomidine, dexamethasone, and control groups, respectively. We determined a sample size of 135 patients total at 95% confidence interval, 80% power, and 20% dropout rate (Appendix A). Thus, the number of patients recruited per group was 45. This was calculated using the F tests—analysis of variance (ANOVA): fixed effects, omnibus, one-way method of the G*Power 3.1.9.7 software (Heinrich Heine University, Dusseldorf, Germany).

Statistical Analysis

The SPSS version 23.0 was used to analyze data (IBM Corp., Armonk, NY, USA). The normally distributed variables like age and weight were described using mean and SD and compared using one-way ANOVA test. Non-parametric data like the duration of analgesia and duration of anesthesia were described using the median and interquartile range and compared using the Kruskal–Wallis test. Nominal data like sex and types of surgeries were described using frequency and compared using the Chi-square test. Comparison of FLACC scores across various time points was assessed using Repeated Measures ANOVA with Tukey’s post-hoc test. The time required to restore analgesia was determined using survival analysis. The log-rank (Mantel–Cox) test was utilized for pairwise comparisons between groups. The hazard ratios were determined using the Cox regression model. In statistical terms, a P-value < 0.050 (two-sided) was considered a significant indicator.

Results

Out of 140 patients scheduled for surgery, 5 were excluded (3 did not match the requirements for inclusion, 1 refused to participate, and 1 had a neurological disorder). As a result, 135 patients (45 in each group) were included in the study (Figure 1). We did not encounter an unsuccessful block. The individuals included in the research had comparable baseline characteristics (Table 1). The duration of anesthesia did not vary between groups (Table B1 in Appendix B).

The median analgesia duration was comparatively prolonged in the RD and RM group (600.0 [480.0–720.0] minutes and 600.0 [480.0–720.0] minutes, respectively) compared to the R group 360.0 (300.0–480.0) minutes (P < 0.001) (Figure 2). However, no significant difference in analgesia duration was seen between the RD and RM groups. There were no differences in the hemodynamic parameters (HR and MBP) between the research groups at different time intervals (Figures B1 and B2 in Appendix B).

The results show a significant difference in the FLACC scores measured across the various time points in the three groups (F [21.82, 8.82] = 1.99, P = 0.040) (Figure 3). On post-hoc test using Tukey’s method, a significant difference was noted between RD and R (P = 0.006) and between RM and R groups (P = 0.011) but not between RD and RM groups (P = 0.980).

On Kaplan–Meier analysis (Figure 4), the mean survival time to rescue analgesia was 403.80 minutes (standard error [SE], 0.463) in the R group, 563.40 minutes (SE, 0.461) in the RD group, and 644.40 minutes (SE, 0.332) in the RM group (P < 0.001). A log-rank test (Mantel–Cox) was run to determine pairwise differences in survival distribution across the groups. It was found that the mean survival time to rescue analgesia was significantly lower in the R group as compared to the RD group (Chi-square, 9.75, P = 0.002) and the RM group (Chi-square, 22.588, P < 0.001). There was no significant difference between the RD and RM groups (Chi-square, 3.46, P = 0.063).

The rescue analgesia was administered only when the FLACC score was more than 4 on two occasions. In RD, RM, and R groups, 4, 0, and 22 patients needed 4 doses; 6, 10, and 13 patients required 3 doses; 21, 16, and 6 patients needed 2 doses; and 9, 15, and 3 patients required only one dose of rescue analgesia in the 1,440 minutes of the postoperative period, respectively. Five children in RD, 4 in RM, and only one in the R group did not need rescue analgesia (Figure B3 in Appendix B).

The postoperative sedation score was evaluated using the RSS at different time intervals. On repeated measures ANOVA, a significant difference was found in the RSS measured across the various time points in the three groups (F [10.17, 4.42] = 14.21, P < 0.001) (Figure 5). Postoperative sedation was more in the RM group up to 120 minutes postoperatively compared to RD and R groups. On Tukey’s post-hoc test, a significant difference was found between RD and RM (P = 0.001) and RM and R (P < 0.001) but not between RD and R (P = 0.118).

None of the groups had adverse events such as bradycardia, hypotension, or respiratory depression. Only 2 children in the RD group had nausea and vomiting.

Discussion

In this study, we investigated two non-opioid adjuvants (dexmedetomidine vs. midazolam) with ropivacaine in the caudal block for children undergoing lower abdominal surgeries. We found only one study in the literature that compared these two non-opioid adjuvants with bupivacaine, conducted by Oruobu-Nwogu et al.¹¹ However, the sample size in their study was only 66, and they did not compare the sedation across these groups. Our study had a large sample size of 135 patients and compared RSS scores between the study groups. Furthermore, we compared pain scores for a more extended period, up to 1,440 minutes postoperatively, in contrast to Oruobu-Nwogu et al.¹¹, who compared it for only 120 minutes.

Sanwatsarkar et al.¹³ observed a period of analgesia of 724.80 ± 60.29 minutes in the clonidine-bupivacaine group, 605.40 ± 82.37 minutes in the midazolam-bupivacaine group, and 295.00 ± 41.78 minutes in the bupivacaine group in the caudal block for children in infraumbilical surgeries. The results obtained in their study were comparable with our investigation. They found a higher FLACC score in the bupivacaine group compared to the midazolam and clonidine groups. In our research, the FLACC score was comparatively higher in the ropivacaine group than in the midazolam and dexmedetomidine group postoperatively in the first 360 minutes.

Krishnadas et al.¹⁴ did a similar study for the caudal block using ropivacaine with midazolam, ropivacaine with tramadol, and ropivacaine. The average time to rescue analgesia was comparatively more significant in the midazolam-ropivacaine and ropivacaine-tramadol group (769.0 ± 331.9 minutes and 913.0 ± 315.5 minutes, respectively), whereas the ropivacaine group was 437.00 ± 75.68 minutes. Their findings were comparable to those of the present investigation.

Al-Zaben et al.¹⁵ evaluated the analgesic potential of dexmedetomidine as an adjunct to bupivacaine at two different doses, 1 µg/kg and 2 µg/kg. In our study, we used 1 µg/kg of dexmedetomidine, which had an excellent hemodynamic profile intraoperatively and postoperatively with good-quality of analgesia.

Anand et al.¹⁶ examined the efficiency of dexmedetomidine (2 µg/kg) in conjunction with ropivacaine in the caudal block, while we employed dexmedetomidine at a dosage of 1 µg/kg in our research. The results obtained were comparable to our investigation. They noticed that the period of analgesia was extended in the ropivacaine-dexmedetomidine group (870 vs. 330 minutes) compared to the group that received only ropivacaine. The period of analgesia in the dexmedetomidine-ropivacaine group was 600.0 (480.0–720.0) minutes in our study, which was significantly prolonged compared with the ropivacaine group.

Our study showed that the time for the first rescue analgesia was more in the dexmedetomidine-ropivacaine group and midazolam-ropivacaine group. Oruobu-Nwogu et al.¹¹ in their study found the longer time for first rescue analgesia in the dexmedetomidine-bupivacaine group, followed by midazolam-bupivacaine, and the shortest in the bupivacaine group in the caudal block. This can be due to different doses of adjuvant used, i.e., 1.5 µg/kg dexmedetomidine and 50 µg/kg midazolam in their study.

Imani et al.¹⁷, in their study on 46 children, performed caudal block using ropivacaine (R group) or ropivacaine plus 2 µg/kg dexmedetomidine (DR group). They defined analgesia duration as pain score < 3. They found that the period of pain relief was substantially more in the DR group than in the R group (P = 0.001). Similarly, we observed that dexmedetomidine substantially prolongs analgesia in the caudal block. They noticed that the pain score in the DR group was less than the R group at 360 minutes, similar to our findings.

Bano et al.¹⁸ evaluated the analgesia of caudal bupivacaine with caudal bupivacaine-midazolam mixture. Their observations were similar to our study results which showed a more extended period of analgesia in the midazolam-bupivacaine group with higher sedation up to 120 minutes postoperatively. Our study results were consistent with Sanwatsarkar et al.,¹³ who observed that the sedation was more in the bupivacaine-midazolam group in the caudal block. The sedation in the RM group was arousable and can be deemed safe.

Both caudal dexmedetomidine and midazolam have been shown not to cause respiratory depression or hemodynamic alterations when used in conjunction with ropivacaine. Only 2 patients in the RD group had vomited, but none from the RM or R group had vomited in the postoperative period.

This study has the merit of being an adequately powered randomized controlled trial. The study also had certain limitations, such as the fact that it was done in a single center. Because we used a single-shot caudal block, we could not generalize our results to continuous blocks. Even though we did not come across any failed block, the procedure under ultrasound guidance will be more accurate. FLACC pain score is sometimes subjective, and the time points of measurement could be interfered by participants’ activities during sleeping and movement. We would have considered other more objective measurements, such as the time of first oral intake or pain levels during movement. Through their diverse mechanisms of action, adjuvants may have analgesic effects on systemic absorption after caudal block. We did not assess the amounts of midazolam and dexmedetomidine in the cerebrospinal fluid or plasma. Further research should be conducted to determine the optimal dosages and study both medicines in continuous blocks.

We conclude that combining dexmedetomidine or midazolam with ropivacaine prolongs analgesia in the caudal block for infraumbilical surgeries in children; however, the analgesia duration was not significantly different between these two drugs combination.

Acknowledgments

None.

Conflict of Interest

All authors declared no conflicts of interest.

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References

Appendix