Caudal Additives in Pediatrics: A Comparison Among Midazolam, Ketamine, and Neostigmine Coadministered with Bupivacaine

Abstract

Single-shot “kiddie caudal” with bupivacaine alone is losing popularity because of its duration of 4–8 h. In a prospective randomized double-blind clinical study, we assessed and compared the efficacy of ketamine, midazolam, and neostigmine coadministered with bupivacaine in a caudal epidural to provide intraoperative and postoperative pain relief. Eighty children (ASA status I) aged 5–10 yr undergoing unilateral inguinal herniotomy were allocated randomly in equal numbers (n = 20) into 4 groups to receive a caudal injection of 0.25% bupivacaine (1 mL/kg) with or without ketamine (0.5 mg/kg), midazolam (50 μg/kg), and neostig-mine (2 μg/kg), after the induction of standardized general anesthesia without premedication. Monitoring for pain, sedation, postoperative nausea/vomiting, dizziness, and pruritus was performed by anesthesiologists blinded to the study allocation. The time to first analgesic administration (paracetamol syrup) was longer (P < 0.05) in the bupivacaine-neostigmine group and the bupivacaine-midazolam group than in the other groups. Undesirable effects, such as emesis, pruritus, and dizziness, were comparable in all groups. However, the incidence of hallucination was more frequent in the bupivacaine-ketamine group compared with the other groups. This study shows that single-shot caudal coadministration of bupivacaine-neostigmine and bupivacaine-midazolam was associated with an extended duration of postoperative pain relief.

In Brief

IMPLICATIONS: The addition of opioids and non-opioids to local anesthetics can prolong the duration of pain relief of caudal epidural blocks. Each of the three non-opioids compared in this double-blind study prolonged the duration of analgesia. However, neostigmine and midazolam were more effective than ketamine.

Single-shot caudal anesthesia with local anesthetic (bupivacaine) is the most commonly used regional technique for intraoperative and postoperative pain relief in children. The popularity of this technique is due to its simplicity and frequent success (^1,2). However, the single-shot “kiddie caudal” may have only a short duration of action (³). Placement of a catheter into the caudal epidural space adds to the risk of infection and tends to prevent early mobilization (⁴); hence, it is not very popular. Therefore, >60% of children undergoing groin surgery with this technique require further analgesia during the postoperative period (⁵). Prolongation of analgesia by using this technique has been achieved by the addition of various adjuvants. The addition of opioids significantly prolongs the duration of caudal analgesia; however, it has a number of unpleasant side effects, as well as the risk of late respiratory depression (⁶). Attempts to overcome these problems by combining bupivacaine with other non-opioids, such as clonidine (⁷), ketamine (⁸), midazolam (⁹), and neostigmine (¹⁰), have met with different degrees of success, as reported by different investigators, in prolonging the pain-free period. However, no single study has compared the non-opioid adjuvants to discover the most suitable drug to be coadministered with bupivacaine for single-shot kiddie caudal for intraoperative and postoperative analgesia.

Therefore, this study was designed to compare the effects of the addition of midazolam (50 μg/kg), ketamine (0.5 mg/kg), or neostigmine (2 μg/kg) on the duration of caudal block produced by 0.25% bupivacaine 1 mL/kg. Clonidine was not included to this study because of its unavailability in our country in the injectable form.

Methods

The study was approved by the local ethics committee, and written informed parental consent was obtained for each subject. We studied 80 boys, ASA physical status I, aged 5–10 yr, scheduled to undergo elective unilateral inguinal herniotomy as inpatients. Exclusion criteria included contraindication to caudal block.

No premedication was prescribed to any child, and all procedures were performed under general anesthesia. Anesthesia was induced with N₂O, oxygen, and halothane. After IV access was secured, the boy was turned to the left lateral position. Caudal block was performed by a consultant anesthesiologist by using a 23-gauge short-bevel needle under aseptic conditions. Tracheal intubation was then performed after the administration of atracurium 0.5 mg/kg. Anesthesia was maintained with 70% nitrous oxide in oxygen and halothane 0.5%–1%, with intermittent positive-pressure ventilation. No intraoperative sedatives or opioids were administered.

The study design was randomized and double-blind: patients were randomly allocated to 1 of the 4 groups (n = 20) by using a random number table. An anesthesiologist not involved in patient care prepared the study solutions by following standard written instructions. Group bupivacaine (B) received caudal injection of 0.25% bupivacaine 1 mL/kg; in addition, Groups bupivacaine-midazolam (BM), bupivacaine-ketamine (BK), and bupivacaine-neostigmine (BN) received preservative-free midazolam 50 μg/kg, preservative-free racemic ketamine 0.5 mg/kg, and neostigmine (containing methylparaben and propylparaben preservatives) 2 μg/kg, respectively. A small Elastoplast dressing was placed at the site of injection in all patients. The association of saline was not necessary because the methodology was based on a final caudal volume, which was similar in all groups. Surgical intervention started 10–15 min after the injection.

Heart rate (HR), mean arterial blood pressure (MAP), and peripheral oxygen saturation (Spo₂) were recorded before the anesthesia induction and every 5 min after the placement of caudal anesthesia. During surgery, adequate analgesia was defined by hemodynamic stability, as indicated by the absence of an increase in MAP or HR by >15% of preincision baseline values; halothane concentration was maintained between 0.5% and 1%. An increase in HR or MAP within 15 min of skin incision indicated failure of caudal anesthesia. If the readings increased by >15%, the child received a rescue opioid (fentanyl; 2 μg/kg initially and subsequently 0.5 μg/kg as dictated by hemodynamic variables), because analgesia was considered inadequate. Fluid therapy was standardized during and after surgery. During surgery, children received lactated Ringer's solution 6 mL · kg⁻¹ · h⁻¹, whereas 5% dextrose in 0.45% NaCl was infused at 4 mL · kg⁻¹ · h⁻¹ in the postoperative period. An intraoperative decrease of MAP or HR by >30% was defined as hypotension or bradycardia, respectively, and was treated by fluid bolus, ephedrine, or atropine, as necessary.

Each patient was observed for 2 hours in the recovery room before being transferred to the ward. HR and Spo₂ were monitored continuously, and MAP was monitored every 5 min. When the child was awake in the recovery room, pain and sedation scores, respiratory rate, MAP, and HR were assessed by an anesthesiology resident who was blinded to the group allocation. Assessments were repeated at 2, 4, 6, 12, and 24 h after recovery from anesthesia by the same anesthesiology resident. The same person performed the measurements in all patients. Postoperative pain was assessed with a 5-point verbal pain score (¹¹): 1 = asleep; 2 = awake, but no pain; 3 = mild pain; 4 = moderate pain; and 5 = severe pain. The visual analog scale (10-cm horizontal scale) could not be used in our study because it was not well understood by all children in the study. The duration of absolute analgesia was defined as the time from caudal injection until the pain score was ≤2. Rescue analgesic was given for a pain score ≥4 in the form of oral paracetamol (20 mg/kg) as necessary. Sedation scores (0 = eyes open spontaneously, 1 = eyes open in response to verbal stimulation, 2 = eyes open in response to physical stimulation, and 3 = unarousable) were also measured, along with pain. Motor block was assessed on awakening by using a modified Bromage scale (¹²) that consisted of 4 points: 0 = full motor strength (flexion of knees and feet), 1 = flexion of knees, 2 = little movement of feet only, 3 = no movement of knees or feet. However, younger children who could not move their legs on command were stimulated on the legs and feet.

The incidence of adverse effects such as nausea, vomiting, dizziness, and pruritus was evaluated by a yes/no survey. Respiratory depression was defined as a respiratory rate of <10 breaths/min. All evaluations were performed along with assessments of pain and sedation.

The sample size was determined with a target to detect a prolongation of postoperative analgesia by 200 min compared with placebo, with a power of 0.88 and a P value of 0.05. Data were analyzed by analysis of variance with Fisher's exact test for nominal data and the Kruskal-Wallis test with Bonferroni's correction for ordinal data. A value of P < 0.05 was regarded as a statistically significant difference.

A follow-up study was undertaken to detect any adverse neurological outcome in the study population. This follow-up consisted of a questionnaire to parents (any movement abnormality; child complaining of any abnormal sensation, such as pain [any sort of pain, without an obvious injury or lesion], paresthesia, or weakness; any loss of bladder or bowel function; dislike for outdoor sports) and a physical examination, which consisted of observations of movements, tests of motor power, reflexes, position, vibration, and temperature sense. Tests for position, vibration, and temperature were performed in children who could comprehend the directions given to them. Seventy-two children attended the follow-up after 2 mo.

Results

There were no differences among groups in age, weight, HR, and MAP during the study period. The duration of surgery and duration of general anesthesia were also similar. None of the patients showed bradycardia or hypotension. Oxygen saturation (≥97%) was always within the clinically acceptable range (P > 0.05; Table 1). No motor block was seen in any group on awakening and throughout the study period.

Table 1: Patient Data

There were no significant differences among the groups in postoperative sedation scores (P > 0.05). Both the duration of absolute analgesia and the time to first analgesic was significantly prolonged in Group BN (442 ± 31 min; 19.6 ± 4.2 h), Group BM (376 ± 24 min; 16.8 ± 3.9 h), and Group BK (336 ± 16 min; 11.6 ± 4.4 h) compared with Group B (238 ± 22 min; 7.6 ± 5.2 h) (P < 0.05) (Table 2). Groups BN and BM had a significantly longer time to first analgesic compared with Group BK (P < 0.5). However, there was no significant difference between Groups BN and BM (P > 0.05), although the duration of pain relief was greater in Group BN compared with Group BM.

Table 2: Postoperative Pain Relief (mean ± se)

The incidence of vomiting (three patients in Group BN, two patients each in Groups BK and B, and one patient in Group BM) was not significantly different among groups. However, two patients in Group BK experienced hallucinations. No other side effects were observed during the study period. The follow-up evaluations after 2 mo did not show any adverse neurological outcome.

Discussion

In this study, we have confirmed the findings of others that the addition of midazolam 50 μg/kg, ketamine 0.5 mg/kg, or neostigmine 2 μg/kg to caudal bupivacaine prolongs the duration of analgesia. Our results are in accordance with previous published results (^8–10). This is the first study to compare the effects of a specific dose of midazolam, ketamine, and neostigmine on the duration of caudal block. Our results indicated that neostigmine has the most pronounced action among the study drugs. However, we recognize that the doses of study drugs may not have been equipotent. Ketamine, a phencyclidine derivative, has structural similarities to bupivacaine and has some local anesthetic effects (^13,14). The primary mechanism of action is through the blockade of N-methyl-d-aspartate receptors situated in the substantia gelatinosa of the spinal cord (^15–17). Ketamine also binds to the opioid receptors, with a preference for the μ receptors (⁶). Although different doses of ketamine (0.25%–1.0%) (⁶) have been reported in combination with local anesthetics to increase the duration of analgesia, the optimal dose is probably 0.5 mg/kg (^6,18,19).

Midazolam, a benzodiazepine, exerts its analgesic effects when administered epidurally, through the gamma-aminobutyric acid-A/benzodiazepine system in the spinal cord, particularly in lamina II of the dorsal horn (⁶). The mechanism of analgesia may also involve opioid receptors (²⁰). A dose of 50 μg/kg appears to be the optimum dose for epidural administration (⁶); larger doses are associated with prolonged sedation (²¹).

Neostigmine, a cholinesterase inhibitor, exhibits antinociceptive action when administered neuraxially (¹⁰). The mechanism of neuraxial action is not clear, but autoradiographic studies reveal the existence of muscarinic receptors, both M₁ and M₂, in laminae II and III of the spinal cord (^22,23). However, caudal neostigmine appears to have a reasonably benign side-effect profile. Dose-dependent nausea and vomiting are the only reported adverse effects (²⁴). We did not observe any serious adverse effects, possibly because of the limited number of subjects and the small dose of neostigmine used. Neostigmine with methylparaben and propylparaben as preservatives has been safely administered in children (¹⁰). In our study, we did not find any adverse neurological effect in a two-month outpatient evaluation after surgery. The dose of neostigmine used in our study was based on the study of Lauretti et al. (²⁵) such that although effective analgesia is provided, the incidence of adverse effects is minimized. A potential advantage of central neuraxial neostigmine is that it may counteract local anesthetic-induced hypotension by an inhibitory effect on the sympathetic nerve activity and tends to increase the respiratory rate (¹⁰). In this study, the observed perioperative hemodynamic stability with the use of caudal bupivacaine plus neostigmine supports this contention.

We included only elective, unilateral inguinal herniotomy in our study to avoid the type, nature, and duration of pain associated with different types of surgery. Moreover, all cases were performed by the same surgical team to minimize the differences in tissue handling. Furthermore, all observations were performed by a single observer to eliminate the interobserver variability. Thus, we can assume that the difference in pain relief reflects the effectiveness of the antinociceptive measures only.

A weakness of this study is that the doses selected for the adjuncts (midazolam, neostigmine, and ketamine) were derived from the literature, with the assumption that these doses represent the optimal doses of these drugs. Because a dose-response curve for each adjunct was not performed, the administered adjuncts may not have been equipotent.

In conclusion, this study demonstrates that the addition of midazolam (50 μg/kg), ketamine (0.5 mg/kg), or neostigmine (2 μg/kg) to caudal bupivacaine significantly prolongs the duration of effective analgesia. The effect is most pronounced with neostigmine and midazolam.