Dexmedetomidine and Ketamine as an Adjuvant to Levobupivacaine for Pediatric Caudal Analgesia: A Randomized, Controlled Study.

BACKGROUND: Ketamine and dexmedetomidine as an adjuvant to caudal block are used in the pediatric population. AIMS: We aimed to compare the analgesic and safety profile of dexmedetomidine with ketamine for single-shot caudal block. SETTINGS AND
DESIGN: This was a randomized controlled study conducted in a tertiary care university hospital.
MATERIALS AND METHODS: Ninety patients admitted for routine infraumbilical surgical procedures under general anesthesia were enrolled in this double-blind randomized study. Following caudal block under general anesthesia, patients were allocated to one of three groups; Group LS received 0.75 mL.kg - 1 levobupivacaine 0.25% diluted in saline 0.9%, Group LK received 0.75 mL.kg - 1 levobupivacaine 0.25% with ketamine 0.5 mg.kg - 1, and Group LD received 0.75 mL.kg - 1 levobupivacaine 0.25% with dexmedetomidine 1 μg.kg - 1. Postoperative pain was assessed by the Face, Legs, Activity, Cry, and Consolability (FLACC) score, and the duration of analgesia (time from caudal block to time at which FLACC score 4 or more) was recorded. Hemodynamic parameters and oxygen saturation were also monitored. STATISTICAL ANALYSIS USED: Categorical data were analyzed by Chi-squire test and numerical continuous data were analyzed by Student's t-test for comparison between two groups. Mann-Whitney test was used to compare score. One-way analysis of variance was used to compare the means between three groups.
RESULTS: The addition of dexmedetomidine and ketamine to levobupivacaine resulted in significant prolongation of postoperative analgesia duration (467 min and 385 min, respectively) compared with 0.25% levobupivacaine alone (276 min). No significant side effects requiring intervention were observed in any group.
CONCLUSIONS: Dexmedetomidine as an adjuvant to levobupivacaine provides a longer duration of analgesia as compared to ketamine without any significant side effect. Copyright:

INTRODUCTION

Postoperative pain management is an integral part of practice of pediatric anesthesiologists. Various methods and medications that have been tried to provide postoperative pain relief in the pediatric population are not devoid of significant side effects.

Caudal epidural anesthesia is the most commonly practiced regional technique in children for infraumbilical surgeries. However, the limited duration of analgesia following a single injection of local anesthetics mandates the quest for an adjuvant that may prolong it safely. The use of an indwelling catheter for prolonging the duration of action of local anesthetics is usually not practiced due to concerns about proximity to the anorectal area giving rise to infection and toxicity risks in the young population.[1]

In recent years, the addition of adjuvants such as opioids, ketamine, and alpha-agonists to local anesthetics has resulted in prolonging the duration of block, improved pain control, parental satisfaction, and faster recovery.

Levobupivacaine is an amino-amide local anesthetic drug belonging to the family of n-alkyl-substituted pipecoloxylidide. It is the S-enantiomer of bupivacaine. It has shown similar potency to bupivacaine with a lower risk of cardiovascular and central nervous system toxicity.

Ketamine is a selective antagonist of N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. It binds specifically to dizocilpine (MK-801) of NMDA receptor, near the channel pore, and is an uncompetitive antagonist.[2] Besides NMDA receptor antagonism, it directly interacts with μ, δ, andϏ opioid receptors.[3]

Dexmedetomidine is dextrorotatory S-enantiomer of medetomidine. This alpha 2-adrenergic receptor (α2-AR) agonist produces clinical effects after binding to G-protein-coupled α2-AR, of which there are three subtypes (α2A, α2B, and α2C) with each having different physiological functions and pharmacological activities.[4] These receptor subtypes are found ubiquitously in the central, peripheral, and autonomic nervous systems, as well as in vital organs and blood vessels.[5] The locus ceruleus of the brain stem is the principal site for the sedative action and the spinal cord is the principal site for the analgesic action, both acting through α2A.[4] α2-AR agonists have been successfully used in several clinical settings in view of diverse actions which include sedation, analgesia, anxiolysis, perioperative sympatholysis, cardiovascular stabilizing effects, reduced anesthetic requirements, and preservation of respiratory function.[6]

The most commonly used drugs as adjuvants are clonidine, ketamine, and opioids. In our practice, ketamine and dexmedetomidine are administered as an additive to improve the duration and quality of analgesia. Both have sedative action but somewhat opposite effects on the cardiovascular system. As the safety margin is less in the pediatric population, this study aimed at evaluating the efficacy of caudal dexmedetomidine versus ketamine for postoperative pain relief in pediatric patients as an adjuvant with levobupivacaine. We compared levobupivacaine 0.25% alone, levobupivacaine 0.25% with ketamine 0.5 mg.kg−1, and levobupivacaine 0.25% with dexmedetomidine 1.0 μg.kg−1 as a single-shot caudal block in infraumbilical surgeries in children aged between 3 months and 7 years of age.[78] The secondary objective was to assess their cardiovascular safety profile.

MATERIALS AND METHODS

This study was conducted after obtaining ethical clearance from the Institutional Ethics Committee (No. 854/Acad. dated July 24, 2017) during the period from December 2017 to June 2019. The trial was registered before patient enrollment with Clinical Trials Registry – India (ctri.nic.in) vide registration number CTRI/2017/09/009902. Written informed consent was obtained from all the parents before enrollment for the study.

Ninety patients admitted for routine infraumbilical surgical procedures under general anesthesia, who fulfilled the inclusion criteria, were enrolled in this double-blind randomized, controlled study conducted in a tertiary care university hospital.

Patients of ASA physical status 1 and 2, between 3 months and 7 years of age of either sex, in whom caudal block was indicated and whose parents were able to comprehend and willing to participate were included in the study. The exclusion criteria included known sensitivity to any of the study drugs, presence of infection at the site of caudal block, coexisting coagulopathy, or any neurological condition or failed block.

On arrival to the operation theater, the standard monitors, i.e., lead II electrocardiogram, noninvasive blood pressure, and pulse oximeter, were attached and the baseline parameters were recorded. General anesthesia was induced using fentanyl 2 μg.kg−1, along with sevoflurane (inhalational) or propofol (intravenous). Tracheal intubation was facilitated with atracurium 0.5 mg.kg−1. Anesthesia was maintained with nitrous oxide and sevoflurane in oxygen along with intermittent positive pressure ventilation.

Under strict aseptic precautions, caudal block was performed. By the use of sealed envelope technique based on computer-generated random numbers, patients were allocated to one of three groups; Group LS received 0.75 mL.kg−1 levobupivacaine 0.25% diluted in saline 0.9%, Group LK received 0.75 mL.kg−1 levobupivacaine 0.25% with ketamine 0.5 mg.kg−1, and Group LD received 0.75 mL.kg−1 levobupivacaine 0.25% with dexmedetomidine 1 μg.kg−1.

Heart rate, mean arterial pressure, and oxygen saturation were monitored continuously. If the patient responded to the surgical incision with a >15% increase in systolic blood pressure or a 15% rise in heart rate, it was planned to give fentanyl 1 μg.kg−1 intravenously.

At the end of the surgery, residual neuromuscular blockade was reversed and the patients were monitored in postanesthesia care unit for 24 h. Heart rate, mean arterial pressure, and oxygen saturation were recorded. Postoperative pain was assessed by the Face, Legs, Activity, Cry, and Consolability (FLACC) score, and the duration of analgesia (time from caudal block to time at which FLACC score 4 or more) was recorded.[9] FLACC score was recorded at 15 min following extubation and then every 30 min for the first 4 h and hourly thereafter till the score was 4 or more, which was considered the end point of the study, and at this point, systemic analgesics were given for analgesia [Table 1].

Table 1

The FLACC pain scale[9]

Categories	Scoring
	0	1	2
Face	Smile or no particular expression	Occasional grimace or frown, withdrawn, disinterested	Frequent to constant frown, clenched jaw, quivering chin
Leg	Normal position or relaxed	Uneasy, restless, tense	Kicking or legs drawn up
Activities	Lying quietly, normal position, moves easily	Squirming, shifting back and forth, tense	Arched, rigid, jerking
Cry	No cry (awake or asleep)	Moans or whimpers, occasional complaint	Crying steadily, screams or sobs, frequent complaints
Consolability	Content, relaxed	Reassured by occasional touching, hugging, or talking to, distractible	Difficult to console

In addition, postoperative side effects, such as nausea and vomiting, and a decrease in oxygen saturation of <90% requiring supplementary oxygen were noted.

Paracetamol 20 mg.kg−1 was administered as rescue analgesic. Rescue antiemetic planned was ondansetron 0.06 mg.kg−1.

Significant bradycardia requiring intervention was defined as fall in heart rate more than 20% from baseline and was planned to treat with injection atropine 0.02 mg.kg−1. Significant hypotension requiring treatment was defined as more than 20% fall in systolic blood pressure from baseline or systolic blood pressure <90 mmHg and was planned to treat with intravenous fluid bolus 10 mL.kg−1 0.9% normal saline.

The primary outcome was comparing the duration of postoperative analgesia using these interventions. The secondary outcome was comparing the hemodynamic changes, i.e., heart rate, mean arterial blood pressure, and oxygen saturation.

The randomization sequence was computer generated, and the drugs were prepared in a double-blinded manner. An anesthesiologist who was not involved in the study and was aware of the children's age and body weight prepared the drugs for the three groups and handed over the unlabeled syringe for caudal administration. The patients' parents and the anesthesiologist, who managed the cases and was responsible for data collection, were unaware of the group allocation.

Statistical analysis

Sample size was calculated on the basis of a previous study that the addition of caudal dexmedetomidine had prolonged the duration of analgesia than the caudal levobupivacaine alone or in combination with caudal fentanyl.[10]

Using PASS 10 for sample size calculation, in one-way analysis of variance (ANOVA) study, the total sample of 90 individuals achieved 80% power to detect differences among the mean duration of analgesia using an F-test with a 0.05 significance level.

Data were analyzed using SPSS version 22.0 (Chicago, USA). Categorical data were analyzed by Chi-squire test and numerical continuous data were analyzed by Student's t-test for comparison between two groups. Mann–Whitney test was used to compare score. One-way ANOVA was used to compare the means between three groups. When using the above statistical tests to compare the mean among the groups, P ≤ 0.05 was considered as statistically significant.

RESULTS

In one patient, the caudal block failed due to anatomical reason. Of the 90 enrolled participants, the results of 89 were analyzed [Figure 1]. Demographically, all groups were comparable and the mean distribution of weight, age, and sex between these groups was not statistically significant [Table 2].

Figure 1

Consolidated Standards of Reporting Trials flow diagram of participants through the study

Table 2

Demographic profile of patients

Variables	Group LD (n=30)	Group LK (n=29)	Group LS (n=30)	P
Age (years)	3.81±2.02	3.19±1.93	3.59±2.15	0.499*
Weight (kg)	13.62±4.98	12.36±4.58	13.51±4.44	0.572*
Sex (male/female)	29/1	28/1	30/0	0.770†

*One-way ANOVA F-statistic, †Chi-square 2 df. ANOVA=Analysis of variance

Table 3 shows the mean duration of analgesia in the three groups as revealed by time taken to achieve FLACC score of 4 or more. Both the LD and LK groups showed a significant prolongation of postoperative analgesia duration (467 min and 385 min, respectively) when compared with the LS group (276 min). This was statistically significant (P = 0.0001).

Table 3

Comparison of time to achieve the Face, Legs, Activity, Cry, and Consolability score (≥4) among groups

	Group LD (n=30)	Group LK (n=29)	Group LS (n=30)	P
Time (min)	467±140	385±165	276±99	0.0001*

*One-way ANOVA F-statistic, P value. ANOVA=Analysis of variance

The mean heart rate, mean arterial pressure, and oxygen saturation of patients in the three groups after 15 min of extubation was not statistically significant [Table 4].

Table 4

Comparison of outcome variables after 15 min of extubation

Variables	Group LD (n=30)	Group LK (n=29)	Group LS (n=30)	P
Heart rate	114.73±26.08	111.00±23.18	101.53±19.31	0.079*
Mean arterial pressure	73.33±7.65	75.03±6.52	72.23±7.15	0.321*
Oxygen saturation	99.30±1.08	99.37±0.91	99.07±0.94	0.447*

*One-way ANOVA F-statistic, P value. ANOVA=Analysis of variance

No patient developed any adverse hemodynamic event or nausea and vomiting necessitating any drug intervention. No patient among the three groups exhibited a decrease in oxygen saturation of <90% requiring supplementary oxygen.

DISCUSSION

FLACC score was used for assessment of postoperative analgesia because it is easy to use and provides objective evaluation. The main finding of our study was the addition of dexmedetomidine 0.1 μg.kg−1 to 0.25% levobupivacaine, and the addition of ketamine 0.5 mg.kg−1 to 0.25% levobupivacaine administered caudally in pediatric patients resulted in significant prolongation of postoperative analgesia duration (467 min and 385 min, respectively) and when compared with 0.25% levobupivacaine alone (276 min). No significant side effects requiring intervention were observed in any group.

After extensive literature search, we were unable to find a similar study conducted to compare ketamine and dexmedetomidine along with levobupivacaine.

Our results are in agreement with a recent review that included 21 publications involving 1590 children.[1] It demonstrated a significant prolongation of the duration of analgesia by a factor of 2.5–3 with the addition of dexmedetomidine to the caudal epidural solution, regardless of the local anesthetic agent used. This effect has been found most commonly with a dose of 1 μg.kg−1.

Another study showed that the addition of 1 μg.kg−1 of dexmedetomidine decreases the effective concentration of levobupivacaine from 0.25% to 0.125% to extend the duration of analgesia.[11] This also allows the use of a lower volume or concentration of the local anesthetic, further reducing the risk of toxicity of local anesthetics.

Dexmedetomidine as an adjuvant to bupivacaine has shown to improve not only the quality of caudal block provides, but also it increases the duration of postoperative analgesia.[8] Similarly, it has been observed that caudal dexmedetomidine with levobupivacaine improves postoperative analgesia in children without any neurological side effects.[12]

In the human spinal cord, α2-AR is more concentrated in the sacral region when compared to the lumbar and thoracic sites, suggesting that their physiologic effects may be potentiated in this region when administered by the caudal epidural route.[13] The analgesic properties of dexmedetomidine result from interactions with the α2-AR within the spinal cord resulting in the decreased release of nociceptive substances. Moreover, dexmedetomidine has an affinity for α2-AR that is eight times that of clonidine making it a better alternative than clonidine for this purpose. The antinociceptive effects of dexmedetomidine relate to its actions on various receptors and ion channels with regional, central, and systemic effects.

We observed patients for 24 h after surgery and concluded that the duration of action of caudally administered ketamine (LK group) was 385 ± 165 min. Similar to levobupivacaine, ketamine also has the advantage of producing effective analgesia with a lower dose of local anesthetic and hence avoiding potential serious complications associated with local anesthetic agents.

Ketamine 0.5 mg.kg−1 added to 0.15% caudal levobupivacaine has been shown to improve the quality of postoperative analgesia and significantly decreases the need for rescue analgesia in the immediate postoperative period as compared to caudal 0.2% levobupivacaine alone.[14] Our study revealed improved analgesia following the addition of ketamine to 0.25% levobupivacaine. This is consistent with previous reports suggesting faster onset and prolonged duration of caudal analgesia with caudal ketamine in association with bupivacaine and ropivacaine compared with local anesthetics alone.[1516] Caudal ketamine in a dose of 0.5 mg.kg−1 also provides prolonged analgesia as compared to fentanyl 1 μg.kg−1 (8.23 h vs. 5.95 h) when added to bupivacaine.[7]

Another study concluded that the addition of ketamine 0.5 mg.kg−1 to caudal bupivacaine 0.25% in a dose of 1 mL.kg−1 significantly prolonged the postoperative analgesia (10.18 ± 2.24 h) compared with administration of caudal bupivacaine 0.25% in a dose of 1 mL.kg− 1 alone (5.63 ± 0.98 h).[17]

Ketamine local anesthetic combinations have been shown to speed the onset of analgesia, prolong the duration of caudal analgesia, and reduce the incidence of ineffective analgesia compared with local anesthetics alone.

In our study, changes in mean heart rate and mean arterial pressure 15 min after extubation in all the three groups were statistically insignificant.

A recent review showed that dexmedetomidine in a dose of 1 μg.kg−1 when added to local anesthetics did not cause respiratory depression in pediatric patients.[1] It provided a longer duration of analgesia as compared to fentanyl and morphine along with a quality of analgesia similar to clonidine without any significant hemodynamic effect. Although postoperative sedation scores were increased following caudal dexmedetomidine, the sedation resulted in improved postoperative behavior scores and decreased emergence delirium.[1]

Our results were similar to another study that showed that the addition of dexmedetomidine to caudal bupivacaine significantly promoted analgesia in children undergoing lower abdominal surgeries and no episodes of clinically significant postoperative respiratory depression, hypotension, or bradycardia were observed.[18]

Similarly, previous studies revealed that caudal ketamine administered along with bupivacaine did not show any effect on the incidence of motor block and neither did show any side effects.[717]

Caudal administration of an adjuvant to enhance the effect of local anesthetic is based on the concept that it will increase the concentration of the drug in the cerebrospinal fluid, producing a more localized effect at the spinal cord level. However, cerebrospinal fluid circulation from the spinal subdural space to the intracranial subdural space may also expose the brain to significant concentrations of these adjuvants. In animal experiments, intrathecal ketamine has shown increased apoptosis in the dorsal horn of neonatal rats and the therapeutic ratio (toxic dose/analgesic dose) of ketamine was calculated to be 1.[19] On the other hand, in the experimental setting, systemic administration of α2-AR (clonidine and dexmedetomidine) has been shown to possess neuroprotective effects against damage caused by hypoxia–asphyxia[20] and by anesthesia-induced apoptosis in the neonatal rat.[21]

Keeping in view the longer duration of action of dexmedetomidine and the potential adverse effects of ketamine, the former appears to be a better alternative in pediatric postoperative pain management.

Our study had several limitations. This study was conducted at a single center that included a small number of patients only. We did not measure the cerebrospinal fluid and plasma levels of ketamine and dexmedetomidine because of logistic reason. Estimation at various time intervals of serum cortisol, blood glucose, and insulin levels might have helped in assessing the stress response.

An additional limitation of our study is that we did not assess the sedation scoring separately.

The patient profile of our study makes it difficult to distinguish between sedation and analgesia as a pain-free child is comfortable and asleep. According to Beyer et al., self-reporting and behavioral pain measures may be discordant in children between 3 and 7 years of age.[22] Further clinical studies are needed to resolve these issues.

CONCLUSIONS

Dexmedetomidine 1 μg.kg−1 as an adjuvant with levobupivacaine 0.25% 0.75 mL.kg−1 provided a longer duration of postoperative analgesia compared to ketamine 0.5 mg.kg−1 when administered for caudal block for infraumbilical surgeries in children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.