Caudal analgesia is a relatively simple technique with a predictable level of blockade, and is by far the most common regional anesthetic used in pediatric surgery for lower abdominal, urological, and lower limb operations . Gradual offset usually provides analgesia beyond the duration of surgery, with a smooth recovery period and good postoperative pain control. This benefit is especially important in ambulatory and same-day surgery patients because it reduces analgesic requirements and facilitates early discharge. However, this technique does depend on the duration of action of the local anesthetic.
Various methods are used to prolong caudal blockade. Routinely, 1:200,000 epinephrine is added to the local anesthetic solution. The advantage is that plasma levels demonstrate diminished systemic reabsorption . In fact, epinephrine prolongs the analgesic effects of lidocaine, but it seems to have little effect on the longer-acting bupivacaine [3,4]. The addition of opioids also prolongs analgesia but carries with it the risk of respiratory depression [5-7]. Ketamine produces analgesia after epidural administration and improves the duration and quality of analgesia provided by bupivacaine in caudal blocks [8,9]; however, the potential for neurotoxic effects after inadvertent intrathecal administration limits its application [10,11].
Clonidine, an alpha2-adrenergic agonist, produces analgesia without significant respiratory depression after systemic, epidural, or intrathecal administration [12-14]. Clonidine's analgesic effect is more pronounced after neuraxial injection, which suggests a spinal site of action and makes this route of administration preferable [12,15]. The addition of clonidine also prolongs the duration of action of bupivacaine after intrathecal and epidural administration in adults . In children, a mixture of 1 mL 0.25% bupivacaine with 1-2 micro g/kg clonidine improves the duration and quality of analgesia provided by caudal block, although results differ widely, ranging from 16.4 hours for 1 micro g/kg  to 5.8 and 9.8 hours for 2 micro g/kg [9,18]. However, clonidine does have the potential to cause hypotension, bradycardia, and respiratory impairment through intense sedation, although these side effects rarely necessitate a drug response in adults. In children, however, hemodynamic data from those studies adding clonidine to caudal blocks are either not available  or cover only the intraoperative  or a three-hour postoperative period . Cardiac output in younger children and infants is relatively dependent on heart rate, making a safety assessment of clonidine in this population necessary before the drug is used extensively as an adjunct to local anesthetic for caudal blockade. We therefore designed a placebo-controlled, dose-ranging study to examine the hemodynamic and respiratory safety of clonidine as an adjunct to bupivacaine caudal anesthesia, and to compare its analgesic efficacy with bupivacaine alone and bupivacaine plus epinephrine.
After institutional approval and informed parental consent, we enrolled 58 pediatric patients aged 0.5-6 yr in a prospective, randomized, double-blind, placebo-controlled study. Patients were scheduled for unilateral ambulatory hernia repair and were randomized to one of five treatment groups for caudal block: 0.75 mL/kg 0.25% bupivacaine (B group), bupivacaine plus 3.75 micro g/kg epinephrine (BE group), bupivacaine plus 1 micro g/kg or 2 micro g/kg clonidine (BC1 and BC2 groups, respectively). Saline 0.75 mL/kg was used as placebo (P group). Drugs were prepared by an anesthesiologist not otherwise involved in the study. One surgeon performed all of the hernia operations, thereby standardizing the technique and surgical patient management.
All children received rectal midazolam 0.75 mg/kg as premedication. Before caudal block, IV access was established under halothane anesthesia administered via face or laryngeal mask, and a glucose/saline solution was infused at the rate of 10 mL [center dot] kg-1 [center dot] h-1. Thereafter, caudal block was performed with a 22-gauge Quincke needle under aseptic conditions with the child in a left lateral position and immediately turned supine after injection of the drug. Anesthesia was maintained with 0.5%-1% halothane and 70% nitrous oxide in oxygen using standard monitoring. Mean arterial pressure (MAP) and heart rate (HR) values were obtained 5 min before the induction of anesthesia (baseline value; 30-45 min after rectal sedation) and every 5 min thereafter during the operation. Patients breathed spontaneously with manual assistance throughout the anesthetic and the surgical procedure. At the beginning of skin closure, anesthetics were discontinued. Once patients were sufficiently awake, they were brought to the recovery room, breathing room air. After arrival, MAP, HR, and percutaneous oxygen saturation (SpO2) were documented every 15 min until 6 h after injection. An intra- or postoperative decrease of MAP or HR more than 30% from baseline values was defined as severe hypotension or bradycardia, respectively, and was treated with a rapid infusion of fluids or, if that was unsuccessful, the use of etilefrine (alpha- and beta-sympathicomimetic drug) in aliquots of 0.02 mg/kg, or atropine 0.01 mg/kg, as appropriate. Respiratory depression was defined as a decrease of SpO2 <93% that required supplemental oxygen via a mask. Analgesic efficacy was documented by an observational pain/discomfort scale (OPS) and by the duration of analgesia after caudal blockade. We used the OPS to assess behavioral objective variables (crying, facial expression, position of torso, position of legs, motor restlessness) . Each variable was scored 1-3 (1 = none, 2 = moderate, 3 = severe) to give a cumulative score of 5-15 with which to qualify analgesia (e.g., 5 = excellent, 15 = ineffective). If the OPS score was >11 in two subsequent measurements or if the patient showed obvious signs of pain, they were given 15 mg/kg rectal paracetamol. Those patients were subsequently eliminated from further evaluation.
The duration of postoperative analgesia was defined as the time between caudal drug injection and the first rectal paracetamol administration. If no rectal paracetamol was necessary within the 6-h observation period, the duration of analgesia was counted as 360 min. A 4-point patient sedation score (PSS) was assigned as follows: 1 = asleep, not arousable by verbal contact; 2 = asleep, arousable by verbal contact; 3 = drowsy/not sleeping; 4 = alert/aware. The PSS was used to quantify sedation and to help to identify side effects, such as respiratory depression from excess sedation. The times from caudal injection to first supported standing and first spontaneous voiding after anesthesia were also documented. Patients were discharged from the recovery room to the ward 6 h after caudal injection and discharged from the hospital within the subsequent 2 h. To achieve an observation period of 24 h, parents were asked to assess the child every 3 h during the 18 h after discharge from the recovery room and to give rectal paracetamol if necessary, or if the OPS score was >11. Parents noted the total requirement for additional analgesics on a form and were contacted by phone or mail within a few days. For the whole study, two observers blinded to the therapeutic interventions were responsible for OPS and PSS assignment, analgesic drug administration, and parental instruction. Each observer performed complete assessments of a single patient during the 6-h observation period.
All hemodynamic data were calculated and compared with the baseline values within each group, as well as with corresponding times among the groups by using the Student's t-test and one-way analysis of variance followed by a post hoc test (Scheffe). Evaluation of OPS, PSS, duration of analgesia, and recovery time of motor function and voiding was accomplished using the Kruskal-Wallis H-test and Mann-Whitney U-test, as appropriate. Proportional data were evaluated by using chi squared and Fisher's exact tests. A P value <0.05 was considered statistically significant.
The study groups were comparable with respect to age, weight, sex, and duration of surgical procedure (Table 1). All patients were sufficiently awake within 15 min and were brought to the recovery room breathing room air. The duration of analgesia was significantly longer in the BC1 and BC2 groups (Figure 1). These two groups also required additional analgesia significantly less frequently during the first 6-h observation period in the hospital and during the subsequent 18-h period at home (Figure 2). Neither duration of analgesia nor postoperative analgesic requirements were different between the B and BE groups. Analgesic efficacy did not seem to be enhanced by increasing the clonidine dose from 1 to 2 micro g/kg. Duration of analgesia (Figure 1), OPS values (data not shown), and postoperative analgesic requirements within the first 24 h (Figure 2) were similar between these two groups. There was a significant decrease from baseline MAP in all groups (range 13%-23%) observed 5-20 min after injection (Figure 3). However, there were no significant intergroup differences in MAP. Conversely, a decrease in HR from baseline was not observed, but there was a marked increase in HR in the P group within the first 90 min after injection (Figure 3). None of the patients required drug therapy to correct hypotension or bradycardia. Those patients receiving analgesic treatment had a comparable degree of sedation (data not shown), except that the BC1 group was different 60 and 75 min after the injection (Figure 4). Respiratory depression was not observed, and SpO2 values were not different among the groups. The times to first supported standing and spontaneous voiding were equivalent among all the groups (Table 2).
Our data indicate that for caudal blockade, the addition of clonidine (1 micro g/kg or 2 micro g/kg) to 0.25% bupivacaine significantly prolongs the duration of analgesia and reduces the postoperative analgesic requirements compared with bupivacaine alone or bupivacaine plus 1:200,000 epinephrine. These findings confirm previous studies [9,18] in which a mixture of 0.25% bupivacaine 1 mL/kg and clonidine 2 micro g/kg produced a longer duration of caudal analgesia in children than bupivacaine alone (9.8 vs 5.2 hours, respectively) or bupivacaine plus epinephrine 1:200,000 (5.8 vs 3.2 hours, respectively). In our study, the addition of epinephrine to bupivacaine affected neither the duration of analgesia nor the postoperative analgesic requirements during the first 24 hours after injection. These findings compare with another study  in which the addition of epinephrine did not prolong bupivacaine's duration of analgesia, but the addition of clonidine did (7.6 vs 16.4 hours, respectively).
One of the purposes for performing the present study relates to the limitations of previous studies. In contrast to our study, previous studies did not include children aged less than 12 months. Premedication either was not uniform  or could have interfered with the analgesic . Inclusion criteria also allowed for diverse procedures  or more extensive lower body surgery, which increases the duration of surgery and the need for perioperative blood and fluid therapy. Even if distributed equally among the groups, all these factors could influence analgesic or hemodynamic variables. We therefore chose hernia repair as a standard pediatric procedure. To investigate hemodynamic safety in younger children, we confined our inclusion criteria for age to a narrower range so that our patients' mean age was considerably lower.
A major shortcoming of our study was the limited time of postoperative assessment because of uniform parental preference for their child's early discharge after the operation. To identify differences in analgesic efficacy earlier, we choose 0.75 mL bupivacaine 0.25% rather than the 1 mL bupivacaine used in the previous studies [9,17,18].
Within the limitations of our study, analgesic efficacy does not seem to be enhanced by increasing the clonidine dose from 1 micro g/kg to 2 micro g/kg. It is possible that the relatively low level of pain caused by inguinal herniotomy made it difficult to separate the analgesic efficacy of the two clonidine doses. From a clinical standpoint, the (insignificantly) reduced need for rescue medications in the BC2 group may be interpreted in favor of the larger clonidine dose. However, the significantly higher OPS values of the P group confirm that effective pain treatment was required. The addition of epinephrine also did not enhance the efficacy of bupivacaine in our study. This finding is consistent with results from other studies of bupivacaine in children and adults [17,20], whereas the addition of epinephrine to short-acting lidocaine greatly prolongs epidural block . The high lipid solubility of bupivacaine may be responsible for the diminished effect of epinephrine. Although vasoconstriction can effectively prevent vascular absorption of hydrophilic lidocaine, lipophilic bupivacaine is also substantially taken up by epidural fat and then slowly released, which contributes to the prolonged duration of action .
One could also argue that parental assessment of acute pediatric pain is less objective than the ratings of professional health care providers . Parental thresholds of reaction to their child's pain may differ widely, and there is evidence that parents administer inadequate analgesic medication even when they recognize that their children are in pain . Furthermore, the behavioral cues on which parents rely to assess pain in their children may differ from those designated on pain scales . However, at home, parents are usually responsible for the treatment of postoperative pain, particularly for children too young to vocalize pain. We attempted to make parental control of the child's pain uniform by instructing parents about the use of our OPS, but the protocol also allowed them to use their own judgment (give rectal paracetamol if necessary, or if the OPS score is >11), although OPS ratings were never less than 12 when parents believed that their children were in obvious pain.
Dose-dependent sedation usually accompanies the use of clonidine for regional anesthesia and likely reflects systemic absorption and vascular redistribution to higher centers, rather than the cephalad migration of clonidine in the cerebrospinal fluid [26,27]. Although clonidine does not cause central respiratory depression per se, the marked sedative effect associated with epidural doses of 300 micro g causes obstructive apnea and arterial oxygen desaturation . We did not observe any of these side effects in our patients, who all had comparable respiratory frequencies and SpO2 values above 93% breathing room air, possibly because 1 micro g/kg and 2 micro g/kg clonidine are well below the dose used in the above-mentioned study. Sedation itself, although not significantly different among the groups receiving analgesics, was slightly more pronounced in the BC1 and BC2 groups. An exception was in the BC1 group 60 and 75 minutes after injection, at which time a significantly larger number of patients scored 1 (indicating strongest sedation) compared with the other groups. However, because sedation made the children look more comfortable, it was actually appreciated by parents and ward staff, and was not regarded as an adverse side effect.
The most undesirable side effects of neuraxial clonidine administration are hypotension and bradycardia . Because cardiac output in younger children and infants depends on HR, a major concern of our study was hemodynamic safety. Furthermore, the combined central and peripheral sympatholytic effect of clonidine plus local anesthetics may cause a more pronounced hemodynamic response than either drug alone. Results from previous hemodynamic studies are either derived from the intraoperative  or early postoperative period  or not described at all . Because data from clinical studies in adults suggest a MAP and HR decrease within 15-30 minutes after epidural injection, which lasts for three hours before returning toward baseline [29,30], we chose a six-hour period with at least 15-minute intervals for MAP and continuous HR monitoring. In our study, the significant decrease of MAP from baseline values occurred in all groups 5-20 minutes after injection, returning to near baseline values within the first hour (Figure 3). However, none of the observed differences among the groups was significant.
These findings are similar to the blood pressure response of adults to clonidine and suggest that the effects of clonidine in children are predictable. Clonidine inhibits sympathetic preganglionic neurons; therefore, the degree of clonidine-induced hypotension is also related to the spinal site of injection. Thoracic epidural administration of clonidine closer to the origin of sympathetic neurons causes a more pronounced MAP decrease than lumbar clonidine administration [29,31,32]. Thus, a more distant caudal site of injection might favor a moderate hemodynamic response to clonidine. Another possibility for the MAP decrease from baseline values is a sympatholytic effect from the local anesthetic. As with clonidine, a more cephalad spread would increase the extent of a sympathetic nerve block. However, hypotension is a rare complication in infants and children less than seven years of age. Even after high thoracic blockade with local anesthetics, cardiovascular stability is believed to depend on the immaturity of the sympathetic nervous system, whereas the parasympathetic nervous system seems to be almost completely differentiated [33-35]. Furthermore, compared with their total blood volume, the amount of pooled blood in the lower extremities is proportionally smaller in children than that of adults . Thus, the observed MAP decrease, even in the P group, is more likely to be related to halothane anesthesia.
The HR response to clonidine in our study is difficult to compare with the response in adults. Some studies report a marked decrease after epidural clonidine, but others do not [29,30,37,38]. In these studies, the changes in blood pressure were dose-dependent and predictable, whereas those relating to HR were transient, variable, and not dose-related. We observed no clinically important decrease in the clonidine groups: only 13% in the BC1 group and 9% in the BC2 group, with the maximal changes occurring 75 minutes after injection. Similarly, children receiving bupivacaine or bupivacaine plus epinephrine 1:200,000 had a very mild HR decrease in our study, if any at all (Figure 3). In children less than eight years of age, the decrease in HR after caudal bupivacaine is less pronounced compared with older children . Our hemodynamic data may have been influenced by the intraoperative use of halothane and postoperative arousal reactions that might have changed the extent of the hemodynamic responses. However, we observed no hemodynamic changes that required drug treatment in either the intraoperative or the six-hour postoperative period.
Neuraxial clonidine prolongs motor blockade of local anesthetics  and can delay recovery of bladder function. All patients could move their legs at the end of the six-hour observation period in the hospital. Standing (with or without support) was sometimes difficult to verify because of the young age of some children; thus, it is conceivable that a weak motor blockade lasted past the discharge time in some children. However, in our study, these effects were comparable with the P group and did not delay discharge.
In conclusion, we were able to demonstrate that for caudal blockade, the addition of clonidine 1 micro g/kg or 2 micro g/kg to 0.25% bupivacaine significantly prolongs the duration of analgesia and reduces the postoperative analgesic requirements compared with plain bupivacaine or bupivacaine plus 1:200,000 epinephrine. Both doses have similar analgesic efficacy and cause equivalent mild hypotension but no significant decrease of HR from baseline. Although there was no significant difference between the two doses, there were fewer rescue interventions required with 2 micro g/kg clonidine added to 0.75 mL/kg 0.25% bupivacaine, compared with 1 micro g/kg clonidine, which suggests that this dose provides greater benefit to the child at no additional risk.
The authors thank Dr. Elise Haidenthaller from Boehringer Ingelheim for providing patients' medical insurance for this study.
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