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Anesth Analg 2007;104:1356-1363
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000261521.52562.de

PEDIATRIC ANESTHESIA

A Comparison of Single-Dose Caudal Clonidine, Morphine, or Hydromorphone Combined with Ropivacaine in Pediatric Patients Undergoing Ureteral Reimplantation

Thomas R. Vetter, MD, Daniel Carvallo, MD, Jodie L. Johnson, MD, Michael S. Mazurek, MD, and Robert G. Presson, Jr, MD

From the Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana.

Address correspondence to Thomas R. Vetter, MD, Department of Anesthesia, Riley Hospital for Children, Room 2001, 702 Barnhill Drive, Indianapolis, Indiana 46202. Address e-mail to tvetter{at}iupui.edu.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Caudal blockade is a common technique for pediatric postoperative analgesia. While safe and effective, caudal opioids are associated with troublesome side effects. Caudal clonidine may offer significant analgesic benefits. We prospectively compared the analgesic, side effect, and rehabilitation profiles of caudal clonidine, hydromorphone, or morphine in a group of 60 pediatric patients undergoing ureteral reimplantation.

METHODS: Patients aged 6 mo to 6 yr were evenly and randomly enrolled in a double-blind manner. Patients received a single caudal dose of 2 mcg/kg of clonidine, 10 mcg/kg of hydromorphone, or 50 mcg/kg of morphine, combined with 1.0 mL/kg of 0.2% ropivacaine with epinephrine. After sevoflurane in oxygen/air anesthesia, all subjects received proxy nurse-controlled analgesia with morphine. Postoperative pain intensity, use of IV morphine, and side effects were assessed during the first 24 h. Oral intake and discharge home were recorded.

RESULTS: Caudal clonidine resulted in less postoperative nausea and vomiting (P = 0.01) and pruritus (P = 0.007) than did caudal hydromorphone or caudal morphine. Caudal morphine produced more sustained initial analgesia than did caudal clonidine (P = 0.02). No difference was observed in pain scores, total morphine use, time to first oral intake or discharge home. No postoperative respiratory depression, excessive sedation, hypotension, or bradycardia was identified.

CONCLUSIONS: Although caudal morphine may result in more sustained initial analgesia, caudal clonidine combined with nurse-controlled analgesia appears to provide comparable analgesia with fewer side effects. Based on these results, the use of caudal clonidine may be superior to caudal opioids after pediatric ureteral reimplantation.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Vesicoureteral reflux is one of the most common congenital anomalies (1). Despite the advent and greater use of subureteral dextranomer/hyaluronic acid (Deflux®) injection (2–5), reimplantation of the ureter onto the bladder (ureteroneocystostomy) continues to be the mainstay of treatment for pediatric patients suffering from vesicoureteral reflux and associated recurrent urinary tract infections (1,6). Postoperative pain control for these patients has historically included the use of an indwelling lumbar or thoracic epidural catheter (7). However, current urologic practice patterns and clinical care pathways encourage a more rapid discharge of patients undergoing ureteral reimplantation (8). For this reason, single-dose caudal analgesia for pediatric ureteral reimplantation has been proposed as an alternative to continuous epidural analgesia (9).

Clonidine, hydromorphone, and morphine are well-accepted neuraxial medications in the pediatric population (10–12). While single-dose caudal opioids have been shown to provide sustained analgesia for a variety of infraumbilical and supraumbilical procedures, their use can result in troublesome side effects (13). The majority of previous pediatric studies of single-dose caudal clonidine have involved urogenital or lower extremity surgery (14). No study has prospectively compared clonidine, hydromorphone, and morphine administered via the single-dose caudal route for a lower abdominal procedure such as pediatric ureteral reimplantation. Therefore, in this prospective, randomized, double-blind study, we compared the analgesic, side effect, and rehabilitation profiles of single-dose caudal clonidine, hydromorphone, and morphine, when each medication was combined with ropivacaine, in a group of pediatric patients undergoing ureteral reimplantation.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After IRB protocol approval and informed parental consent, 60 ASA status I and II patients, aged 6 mo to 6 yr, undergoing ureteral reimplantation (ureteroneocystostomy) for vesicoureteral reflux, were prospectively enrolled in this clinical trial.

Study exclusion criteria included a history of developmental delay or mental retardation, which could make observational pain intensity assessment outside the norm; a known or suspected coagulopathy; an implanted intrathecal pump; the present use of a tricyclic antidepressant or barbiturate; a known allergy to any of the study drugs; and any signs of infection at the site of the proposed caudal block. Study data collection occurred in the day surgery area, the operating rooms, and the inpatient units of a free-standing children’s hospital. All study patients were admitted to the hospital on the day of surgery.

Using a computer-generated number sequence, the 60 eligible and consented patients were randomly and evenly assigned to receive either a single-caudal dose of clonidine combined with ropivacaine (CR group), hydromorphone combined with ropivacaine (HR group), or morphine combined with ropivacaine (MR group). All health care personnel providing direct patient care, the patients, and their parents or guardians were blinded as to the caudal medications administered. Nursing staff involved in the study were educated regarding the use of the observational pain intensity scale and the completion of the study data collection sheets.

All patients received a conventional preoperative dose of oral midazolam (0.5 mg/kg) 20–30 min before anesthetic induction. All patients then underwent a standard inhaled induction with sevoflurane delivered in oxygen and received an IV muscle relaxant. No propofol or thiopental was administered on induction. After endotracheal intubation, patients were placed in the lateral decubitus position, and a single-dose caudal block was performed under sterile conditions using a standard loss of resistance technique. The CR group received 2 µg/kg clonidine, the HR group received 10 µg/kg hydromorphone, and the MR group received 50 µg/kg morphine. Each group also received 1.0 mL/kg (maximum of 30 mL) of 0.2% ropivacaine with epinephrine 1:200,000. Two milliliter of the local anesthetic was initially administered as a test dose. This was followed by the study medication, which had been previously diluted to an equal 1 mL volume with normal saline. The balance of the local anesthetic volume was then given. All caudal blocks were performed by the pediatric anesthesia attending staff member assigned to the surgical case.

General anesthesia was maintained with sevoflurane delivered in oxygen and air. The inhaled concentration of sevoflurane was adjusted based upon intraoperative hemodynamics. No other narcotics, analgesics or sedatives (including fentanyl, morphine, ketorolac, and ketamine) were administered intraoperatively. No intraoperative antiemetic, including ondansetron, was given. All patients had a urethral Foley catheter placed before incision per urology; however, no ureteral stents or drains were placed. The indwelling Foley catheter was removed postoperatively at the discretion of the pediatric urology service. At the conclusion of surgery, the patient was awakened and transported to the postanesthesia care unit (PACU).

The maximum maintenance end-tidal concentration of sevoflurane (%) and the anesthesia emergence time were recorded. The occurrence of any intraoperative hypotension requiring a fluid bolus, bradycardia requiring atropine, and/or a delayed anesthetic emergence (defined as more than 20 min elapsing from the end of surgery to exiting the operating room) was also noted.

Using the pediatric observational FLACC Pain Scale with its 0–10 score range (Fig. 1) (15), each study participant’s pain intensity was assessed by the bedside nurse upon arrival in and at the time of discharge from the PACU. If the patient’s FLACC pain scale score was noted at any time in the PACU to be four or more, up to three IV doses of morphine (30 mcg/kg) were titrated at 10 min intervals to achieve a FLACC scale score of three or less. Proxy nurse-controlled analgesia (NCA) was initiated in the PACU, with a 30 mcg/kg interval dose of morphine, a 20 min lockout period, and a maximum of 12 interval doses per 4 h. The family members of the study subjects were specifically instructed not to participate in the proxy administration of IV narcotic. Once transferred to the inpatient care unit, each study participant’s pain intensity was assessed on the FLACC scale by the bedside nurse at least every 4 h for the first 24 h postoperatively. If however, the inpatient FLACC pain scale score was noted at any time to be four or more, IV morphine was administered via the above-programmed proxy NCA pump. The elapsed time from PACU admission to the first postoperative nurse-administered morphine dose and the total amount of nurse-administered IV morphine during the initial 24 h postoperative period were recorded.


Figure 19
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  		Figure 1. The presently applied FLACC observational pediatric postoperative pain scale (15).

 

Patients were also assessed in the PACU and on the inpatient care unit for bladder spasms and treated as needed with oral oxybutynin (0.05 mg/kg) every 8 h and additionally as needed with oral diazepam (0.07 mg/kg) every 4 h. Postoperative nausea and vomiting (PONV) was treated as needed with IV ondansetron (0.06 mg/kg) every 4 h. Postoperative pruritus was treated as needed with IV diphenhydramine (0.2 mg/kg) every 6 h. Nonsteroidal antiinflammatory drugs (specifically, ketorolac) were withheld for the duration of the study. Oral acetaminophen (10 mg/kg) was administered as needed for a temperature more than 38.5°C.

The duration of PACU admission, PACU admission/ discharge and 4 h postoperative interval FLACC scale scores, as well as the occurrence and the treatment of postoperative bladder spasms, PONV, and pruritus were recorded by the bedside nurse on a dedicated study data collection sheet. The occurrence of any postoperative excessive sedation, respiratory depression, hypotension, and/or bradycardia, requiring medical intervention, was also noted. The initiation of clear liquid and solid food oral intake, the date and time of the removal of the Foley bladder catheter, and the patient’s subsequent discharge home were all recorded.

All continuous group sample data were compared using a one-way analysis of variance (ANOVA) with Tukey HSD post hoc comparisons performed between group means. Kaplan–Meier survival curves of the elapsed time to the first postoperative morphine dose were compared using a log-rank test. Dichotomous group sample data were compared using a {chi}2 test. The FLACC scale pain score data (with a discrete 0–10, minimum to maximum range) were deemed to be ordinal; all of the sequentially obtained individual patient pain intensity score data were aggregated by study group and compared using a nonparametric Kruskal–Wallis test with a Bonferonni correction of {alpha}. Levene’s test (with P < 0.05) was used to confirm the homogeneity of group sample data variance. The Shapiro–Wilk test was applied to assess the normality of the continuous variable data. Any variable found to lack normality was subjected to logarithmic transformation before group mean comparisons. The positive effect of this data transformation on normality was visually confirmed using q-q plots. The collected study data were initially entered into a Microsoft Access database; all statistical analyses were subsequently performed using SPSS 14.0 (SPSS, Chicago, IL) with a P < 0.05 considered significant.

An a priori study sample size calculation was performed based upon our previous retrospectively observed 31% difference in the incidence of PONV in patients receiving a single caudal dose of clonidine versus morphine1. Applying an uncorrected {chi}2 test with an {alpha} of 0.05, a sample size of 30 would be expected to have an 80% power to detect a minimum 30% difference in the incidence of PONV between two such treatment groups. Block randomization was applied so that a preliminary analysis of the primary side effect data could be performed after 60 patients had been enrolled. Based upon this preliminary analysis, enrollment in the study was terminated after 60 patients.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Complete study data were collected on all 60 initially enrolled patients (Fig. 2). While none of the 60 attempted caudal blocks was perceived as being a failed attempt, an intention-to-treat approach was applied that assumed successful caudal block placement. Patient demographics were similar among the three study groups (Table 1). The intraoperative clinical profile was likewise similar among the three study groups (Table 2). Specifically, no significant group difference was observed in the maximum maintenance end-tidal concentration of sevoflurane; the incidence of intraoperative hypotension, bradycardia, or delayed emergence; or the anesthesia emergence time.


Figure 29
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  		Figure 2. Flow of participants through each phase of the study.

 

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  		Table 1. Patient Demographic Data

 

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  		Table 2. Intraoperative Clinical Data

 

There were no observed group differences in either the aggregate postoperative FLACC pain scale scores or the total amount of morphine administered postoperatively via proxy NCA (Table 3 and Fig. 3). While the mean elapsed time from PACU admission to the first required postoperative dose of IV morphine did not differ between the CR group and MR group (P = 0.06) (Table 3), a significant fraction of patients in the MR group experienced postoperative analgesia that was more sustained than in the CR group (P = 0.02) (Fig. 4). A significantly larger percentage of patients in the CR group also required IV morphine in the PACU (P = 0.02) (Table 3).


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  		Table 3. Postoperative Analgesia Data

 

Figure 39
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  		Figure 3. Postoperative observational pain scores. P value generated using Kuskal–Wallis test. Error bars represent 95% CI.

 

Figure 49
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  		Figure 4. Kaplan–Meier curves of the relative duration of caudal analgesia. P value generated using log-rank (Mantel–Cox) test.

 

Patients in the CR group experienced significantly less PONV as compared to patients in the HR group and the MR group (P = 0.01) (Table 4). Patients in the CR group also experienced significantly less postoperative pruritus as compared to patients in the HR group and the MR group (P = 0.007) (Table 4).


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  		Table 4. Postoperative Side Effect and Rehabilitation Data

 

No episode of clinically significant postoperative respiratory depression, excessive sedation, hypotension, or bradycardia was identified. There was no observed difference in the incidence of bladder spasms. The time to first oral clear liquid intake and first oral solid intake was comparable among the three study groups. There was also no observed significant group difference in the time to discharge home.


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
When administered caudally in combination with ropivacaine, a single dose of clonidine was associated with less PONV and pruritus than an equipotent dose of either hydromorphone or morphine. A significant fraction of patients receiving caudal morphine experienced more sustained analgesia as compared to caudal clonidine. No other differences were observed in the postoperative analgesic and rehabilitation profiles. These prospectively collected data confirmed our earlier retrospective findings on the benefits of single-dose caudal clonidine versus single-dose caudal morphine in the pediatric ureteral reimplantation population.

The present caudal doses of clonidine, hydromorphone, and morphine were based upon the published literature (12,14,16–18) and our clinical practice. A much lower (15–30 mcg/kg) caudal dose of morphine may well have resulted in considerably less side effects but similar analgesia (19,20). Previous studies of a lower caudal dose of morphine have, however, primarily involved less extensive and ostensibly less painful urogenital surgery (21–24). The present 50 mcg/kg caudal dose of morphine is consistent with the reported safe and effective use of a 60 mcg/kg caudal dose in a series of children undergoing major orthopedic, thoracic, genitourinary, or abdominal surgical procedures (25).

The hydromorphone to morphine dosing ratio reflected the previously reported five-fold greater epidural bolus potency of hydromorphone (26). The pediatric epidural administration of hydromorphone has been reported to result in less pruritus than morphine (16). Despite its greater lipid-solubility as compared to morphine (26), when administered at the present 10 mcg/kg single caudal dose, hydromorphone resulted in an analgesic and side effect profile comparable to that of 50 mcg/kg of caudal morphine.

Neuraxial opiates are a recognized risk factor for PONV (27,28), and ondansetron has been shown to be effective in reducing the incidence of PONV after a single dose of epidural morphine (29). Although it is common in our practice to administer a prophylactic antiemetic, the prophylactic use of any antiemetic(s) can have variable effectiveness (30,31). For this reason, we relied on a rescue antiemetic, which resulted in an equal risk of PONV among the three study groups and thus permitted the most consistent determination of the occurrence of PONV.

Clonidine has been reported to be an effective adjuvant to caudal analgesia for children undergoing ureteroneocystostomy. In one study of children aged 6 mo–9 yr undergoing bilateral correction of vesicoureteral reflux, 1.5 mcg/kg of clonidine was administered caudally with an equal combination of 0.25% bupivacaine and 1% lidocaine (32). As in our study, the percentage of patients requiring additional analgesia as a function of time was compared using a log-rank test. Not surprisingly, the duration of analgesia in the clonidine group was significantly longer than in the local anesthetic group. In that study, however, a 15% increase in heart rate or systolic blood pressure after 45 min of skin incision was deemed an indicator of inadequate analgesia and resulted in both a rescue dose of 10 mcg/kg of alfentanil and no further study data being collected on that patient. While observational pain scores were recorded during the initial 6-h postoperative period, these data were not reported. No patients receiving caudal clonidine experienced postoperative vomiting; however, side effect data were collected only during the initial 6-h postoperative period.

In a similar more recent study, clonidine was caudally administered with 0.125% bupivacaine in a group of children aged 1–10 yr undergoing ureteroneocystostomy (33). Specifically, patients in the clonidine– bupivacaine group required significantly less IV morphine during the initial 24-h postoperative period than those receiving bupivacaine alone. No group differences were observed in the Wong–Baker FACES Pain Rating Scale and FLACC Pain Scale scores. However, in addition to an initial 1 mcg/kg dose, a second 0.5 mcg/kg dose of clonidine was administered caudally at the conclusion of surgery. Patients also received IV ketorolac at the time of wound closure and for the duration of the study. These differences in study design make comparisons with our findings difficult.

We observed the initial postoperative analgesia to be more sustained after a single caudal dose of morphine as compared to a single caudal dose of clonidine (Fig. 4). We defined the duration of postoperative analgesia as the elapsed time from PACU admission to the first postoperative FLACC pain score of four or more, which per our study protocol resulted in an initial IV dose of morphine. This time frame was deemed to be more clinically relevant than the elapsed time from intraoperative caudal block placement to the first postoperative rescue dose of an analgesic (18,34–37).

The lack of a significant difference in observational pain scores and presumably postoperative analgesia among the three present study groups may be related to our liberal use of IV morphine and the difficulty in measuring pain in children in this age group. Study subjects were afforded sufficient access to IV morphine. This premise is supported by no study patient prematurely reaching their four-hour dosing limit. It can thus be reasonably assumed that parenteral morphine was consistently administered via proxy NCA to the desired analgesic effect. Alternatively, despite its demonstrated postoperative validity (r = 0.80) and interrater reliability (r = 0.94) (15) and its use in a recently published study of pediatric caudal analgesia (38), it is possible that in the present clinical setting, the FLACC Pain Scale was not sensitive enough to discern relevant differences in postoperative pain intensity. Given the number of different bedside nurses who observationally assessed subjects’ postoperative pain, our study would have been strengthened by confirming the intraobserver rater reliability of the FLACC Pain Scale. Previous studies of pediatric postoperative caudal analgesia have alternatively used the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) (39), the Children and Infants Postoperative Pain Scale (CHIPPS) (40), or the Objective Pain Scale (OPS) (41). However, several of these studies likewise observed no significant difference in postoperative observational pain scores (42–47). The underlying issue may be the reported discordance between self-report and behavioral pain measures in children aged 3–7 yr after surgery (48).

Despite the ample published evidence supporting the analgesic benefits of clonidine as a caudal additive (14), at least three studies have failed to observe any such benefit (34,35,49). Specifically, in a group of 2- to 8-yr-old outpatients undergoing urogenital surgery, the addition of 2 mcg/kg of clonidine to 1 mL/kg of 0.125% bupivacaine did not significantly delay the time to first rescue analgesic or decrease the overall need for rescue analgesics (35). In light of these findings, our study might have been strengthened by including a caudal ropivacaine-only control group. However, when compared to local anesthetic alone, the addition of clonidine to a single-dose caudal block has been reported to result in superior postoperative analgesia after pediatric ureteral reimplantation (32).

Caudal epidural blockade remains a widely used technique for providing pediatric postoperative analgesia (50). A number of additives aimed at prolonging the duration of local anesthetic caudal analgesia have been studied in the last two decades (51). However, the continued merit of using caudal-epidural opioids in children has come to be questioned (52). While no single caudal additive appears to be consistently superior to another, based upon its presently observed more favorable side effect profile, the use of caudal clonidine may be superior to caudal opioids after pediatric ureteral reimplantation.


   ACKNOWLEDGMENTS
 
The authors thank Stephanie C. Whittaker, B.S.N. and Susan K. McIlwain, M.S.N. for their invaluable assistance in conducting this study. The authors also express their appreciation for the collegial support and cooperation of the members of the Division of Pediatric Urology at Riley Hospital for Children.


   Footnotes
 
1Annual Meeting of the American Society of Anesthesiologists (2005). A1336: A Comparison of Single-Dose Caudal Clonidine Versus Morphine in Pediatric Ureteral Reimplant Patients. Back

Accepted for publication February 13, 2007.

Presented in part at the 2006 Annual Meeting of the American Society of Anesthesiologists, October 2006, Chicago, Illinois.

Reprints will not be available from the author.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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