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PEDIATRIC ANESTHESIA

A Comparison of Epidural Bupivacaine-Fentanyl and Bupivacaine-Clonidine in Children Undergoing the Nuss Procedure

From the Department of Anesthesiology and Critical Care Medicine and Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Address correspondence to Giovanni Cucchiaro, MD, Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Address e-mail to cucchiaro{at}email.chop.edu.

	Abstract

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX 1 REFERENCES

 
The administration of epidural opioids, though effective for producing analgesia, has severe side effects in most patients. It is unknown whether clonidine can effectively replace opioids and cause fewer side effects. We compared, in this randomized trial, the incidence of vomiting and pruritus as well as the analgesic profile of three different combinations of bupivacaine, fentanyl, and clonidine administered epidurally in patients undergoing the Nuss procedure: bupivacaine + fentanyl, bupivacaine + clonidine, bupivacaine + fentanyl + clonidine. The incidence of side effects was significantly less in the bupivacaine + clonidine group (33%) compared with the bupivacaine + fentanyl (92%) and bupivacaine + fentanyl + clonidine (73%) groups (P = 0.004). Quality of postoperative analgesia was similar in the three groups. No significant complications were observed. In conclusion, clonidine is an effective and safe alternative to epidural opioids.

	Introduction

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX 1 REFERENCES

 
Several studies have been published in the last decades describing the anesthetic-sparing effects and analgesic properties of epidural clonidine. The use of clonidine as an alternative to epidural opioids offers several potential benefits. Clonidine does not have respiratory depressant effects (1,2), and the incidence of vomiting and pruritus is less frequent compared with that seen after administration of epidural morphine (3). Several reports of epidural clonidine have focused on the optimal doses of clonidine to be used (4–6), rather than analyzing the potential advantages of using epidural clonidine versus opioids with respect to efficacy and incidence of side effects (3,7,8).

Epidural fentanyl has been used effectively as an alternative to morphine and has been shown to induce fewer complications when compared with epidural morphine. However, the incidence of vomiting in patients receiving epidural fentanyl still ranges between 28% and 52% depending on the study population and concentration used (9–11). The analgesic and side effects profile of epidural clonidine compared with epidural fentanyl are unknown.

The primary aim of this randomized double-blind trial was to test the hypothesis that epidural clonidine decreases the incidence of side effects compared with epidural fentanyl. Therefore, we compared the effects of the combination bupivacaine-clonidine with those of bupivacaine-fentanyl. The secondary aim of this study was to determine whether the combination bupivacaine-clonidine has the same analgesic efficacy as the combination bupivacaine-fentanyl. To test the hypothesis that a small dose of clonidine may enhance the effects of a small dose of fentanyl, and also reduce the incidence of side effects, we added a third group in which the doses of clonidine and fentanyl were halved. To eliminate possible confounding factors, such as type of incision (thoracic versus abdominal), type of operation (gastrointestinal tract, urinary tract, lung), that could affect the incidence of pain and side effects, we choose to restrict the study only to patients undergoing a Nuss procedure for pectus excavatum repair (12), in whom a thoracic epidural catheter was placed for postoperative analgesia.

	METHODS

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The study was approved by The Children's Hospital of Philadelphia IRB, and written informed consent was obtained from the parent or legal guardian of each patient, along with assent from the subject. Inclusion criteria comprised children 10 to 19 yr of age undergoing a pectus excavatum repair, which required an epidural catheter for postoperative analgesia, and in whom the study medications were infused for at least 8 h after surgery. Exclusion criteria comprised: 1) patients in whom it was impossible to place an epidural catheter, 2) malfunctioning epidural catheter with insufficient analgesia in the postoperative course, 3) patients in whom the epidural catheter was removed within 8 h from the end of surgery.

After mild sedation with oral midazolam (0.5 mg/kg; maximum, 10 mg) and IV fentanyl (2 µg/kg; maximum, 100 µg), a Tuohy 19-gauge needle was used to enter the epidural space at the T6-10 level using a loss-of-resistance technique. A 20-gauge catheter was advanced for 3–5 cm into the epidural space, and correct placement of the epidural catheter was verified with a test dose of 3 mL lidocaine 1.5% with epinephrine 1:200,000. General IV anesthesia was then induced using propofol (3–5 mg/kg) and endotracheal intubation was facilitated with vecuronium (0.1 mg/kg). Anesthesia was maintained with desflurane in 40%–50% air-oxygen.

Patients were assigned to one of the following three treatment groups based on a computer-generated random numbers table: bupivacaine + clonidine (BC), bupivacaine + fentanyl (BF), or bupivacaine + fentanyl + clonidine (BFC). The epidural catheters were filled with 0.3 mL/kg (maximum, 10 mL) of a solution containing the assigned medications (Table 1) and an infusion containing the same combination of medications (Table 1) was immediately started at a rate of 0.25 mL · kg^–1 · h^–1 (maximum, 10 mL/h). The doses of bupivacaine, fentanyl, and clonidine used in this study reflect doses recommended by multiple studies that have analyzed the optimal doses of combined local anesthetic, fentanyl, and clonidine for epidural infusions (13,14). The bolus dose and infusion rates were based on clinical data we collected from patients who underwent a Nuss procedure at The Children Hospital of Philadelphia in the past.

A Foley catheter was placed in every patient and removed after the epidural catheter was discontinued. Episodes of hypotension during the procedure were treated with IV boluses of normal saline (10–20 mL/kg in divided doses) and/or repeated doses of ephedrine (0.1 mg/kg). No opioids were administered during the operation. At the end of the procedure, residual muscle paralysis was antagonized with atropine (20 µg/kg; maximum, 1.2 mg) and neostigmine (70 µg/kg; maximum, 5 mg), the trachea was extubated and patients were taken to the recovery room. On arrival in the recovery room, the epidural catheter was connected to a patient-controlled epidural analgesia device (PCEA) containing the same study solution used during the intraoperative period. The PCEA settings were the same for the 3 study groups: demand 0.05 mL/kg (maximum, 2 mL), basal infusion 0.25 mL · kg^–1 · h^–1 (maximum, 10 mL/h), lockout time 20 min, maximum dose, 0.4 mL · kg^–1 · h^–1 (maximum, 14 mL).

The following variables were monitored and recorded at the time of arrival into the recovery room, 1 h after tracheal extubation, every 4 h for the first 24 h, and every 6 h for the next 48 h:

Arterial blood pressure and heart rate (in both the intraoperative and postoperative periods).

Respiratory rate and oxygen saturation.

Sedation level using the De Kock scale (Appendix #1) (15).

Episodes of vomiting and pruritus and doses of ondansetron and nalbuphine administered.

Level of pain at rest, on mobilization and coughing, evaluated using a visual analog scale (VAS) ranging from 0 to 10 cm with 10 cm being the worst pain imaginable.

Patients' management in the postoperative period was similar in both the recovery room and patient care unit. In case of persistent pain (VAS score >3 cm) patients were examined to determine the sensory level. In case of a sensory level below T2–3, the epidural catheter was filled with 2–4 mL lidocaine 1%. When the sensory level was at T2–3 level and the pain score was >3, patients received nalbuphine 100 µg/kg IV. The administration of nalbuphine was repeated every 4 h if necessary. In case of unilateral block, the catheter was withdrawn 1 cm, and the patient was subsequently reassessed. Patients who experienced vomiting received IV ondansetron (100 µg/kg; maximum, 4 mg) every 8 h, as needed. In case of mild sedation (De Kock sedation scale = 2) the infusion rate of the epidural catheter was reduced by 10%. In case of severe sedation (De Kock sedation scale = 3), the epidural infusion was stopped and patients in whom the oxygen saturation was <95%, supplemental oxygen via nasal cannula was administered. Persistent pruritus was managed with IV diphenhydramine (25 mg), repeated every 6 h as needed. Patients who experienced hypotension received fluid boluses of normal saline (10 mL/kg) in case of arterial blood pressure <80% of the preoperative values. IV ephedrine (5–10 mg) was administered when patients did not respond to the fluid challenge.

We based our sample sizes on the primary outcome measure involving incidence of vomiting during the 48 h after admission into the recovery room. We assumed proportions of vomiting of 0.15, 0.65, and 0.30, respectively, in the 3 groups (BC-BF-BFC). These expected values were obtained from the literature (8–10) and from an analysis of data obtained from children who received epidural infusion at this institution in the past. We used these expected proportions to calculate a variance of proportions (0.038422) and an average proportion (0.387). The test of equality of means was performed at the 0.01 level of significance. When the sample size in each of the 3 groups is 17, a 0.01 level ² test has 80% power to detect a difference in proportions characterized by a variance of proportions of 0.038422 and an average proportion of 0.387.

Data distribution was evaluated for normality by the Kolmogorov-Smirnov test and parametric tests were used when indicated. Continuous data were analyzed with unpaired Student's t-test or analysis of variance as appropriate. Primary statistical analysis was by ² tests of equal proportions in the 3 groups, examining the occurrence of side effects (Yes/No) and the occurrence of required additional treatments due to side effects (Yes/No) among the treatment groups, with Fisher's exact test correction when indicated. The Wilcoxon ranked sum test was used to analyze differences in the number of episodes of vomiting and pruritus during the 48 h in the 3 groups.

	RESULTS

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Of the 67 patients identified who met the inclusion criteria, 47 were enrolled in the study and randomized. The other 20 patients refused to participate in the study. Eight patients were not included in the final analysis: 4 for failure to place the epidural catheter and 4 because of ineffective analgesia from the epidural catheter, which required the removal of the catheter, and the use of IV opioids within the first 8 h after surgery.

An unplanned interim analysis was conducted after 47 patients had been enrolled in the study on the basis of the frequent incidence of side effects. The data analysis showed that the incidence of side effects (vomiting and pruritus) was clinically and statistically more frequent in patients receiving epidural fentanyl compared with patients receiving clonidine. For this reason the investigators decided to terminate the study.

The three groups were similar with respect to patients' age, sex, and weight (Table 2).

The global incidence of side effects (vomiting, pruritus, and severe sedation, as indicated by a score >3) was significantly more frequent in the BF and BFC group compared with the BC group (92%, 73%, and 33%, respectively) (P = 0.004).

The number of patients who experienced vomiting in the study period was significantly less in the BC group (27%) compared with the BF and BFC groups (69% and 55%, respectively) (P = 0.030) (Table 3). No statistical significance was found between the BC (69%) and the BCF (55%) groups (P = 0.2). The number of episodes of vomiting per patient was significantly less in the BC group (0.3 ± 0.6) compared with the BF (2.0 ± 0.6; P = 0.011) and BFC (1.1 ± 0.4; P = 0.01) groups. No difference was found between the BF and BFC groups.

The number of patients who experienced pruritus and required rescue doses of diphenhydramine was significantly less in the BC (0%) group versus the BF (85%) and BFC (54%) groups (P = 0.01) (Table 3). The number of episodes of pruritus per patient was significantly less in the BC versus the BF and BFC groups (0 versus 2 ± 1 and 1 ± 1, respectively; P = 0.01). Patients in the BFC group experienced fewer episodes of pruritus compared with patients in the BF group (P = 0.035).

The incidence and score of sedation were similar in the three groups (Table 3). The study was stopped in two patients because of severe sedation (score = 3): the epidural catheter was removed in a BC patient after 36 h and in a BF patient at 30 h. None of the patients developed episodes of hypoxia.

Patients' VAS scores on arrival in the recovery room were similar in the three study groups (Table 3) (Fig. 1). The VAS score was also similar during the study period (Table 3). The amount of study medication (in addition to the continuous infusion) that each patient received using the PCEA device was also similar in the three groups (Table 3). The number of rescue doses of nalbuphine administered during the study period for VAS more than 3 was similar among the three study groups (Table 3). The cumulative doses of nalbuphine administered were also similar (Fig. 2). The epidural catheter of one patient in the BC, 2 patients in the BF and 3 patients in the BCF groups was filled with lidocaine because of low sensory level and pain during the postoperative period.

View larger version (43K): [in this window] [in a new window]   Figure 1. VAS score by treatment. Values of visual analog pain scale (VAS) in the postoperative period. The dark line indicates the median values. The box represents the 25th–75th percentile and the extended bars the 10th–90th percentile.

View larger version (52K): [in this window] [in a new window]   Figure 2. Cumulative doses of nalbuphine per patient. No significant differences were observed in the requirements of nalbuphine among the three study groups during the study period.

Every patient received 20–30 mL/kg of lactated Ringer's solution during the operation. Eight patients in the BC (53%), 9 in the BF (69%), and 7 in the BFC (64%) groups required ephedrine during the intraoperative period for hypotension (arterial blood pressure <80% of preoperative values). Two patients (one in the BC, one in the BF group) required fluid boluses during the postoperative period for episodes of hypotension.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX 1 REFERENCES

 
The results of the present study demonstrate that it is possible to decrease the unwanted side effects of epidural fentanyl by replacing it with epidural clonidine. The analgesic effects of the combination bupivacaine-clonidine are equivalent to those of the combination bupivacaine-fentanyl.

Cucchiaro et al. (3) have shown that epidural clonidine is superior to morphine with respect to its side effect profile. However, the authors included in the study patients who had undergone a variety of surgical procedures, making it difficult to compare the analgesic efficacy of the two medications. In this study, we included a more homogeneous group of patients. We chose patients undergoing the Nuss procedure for repair of pectus excavatum because the surgery does not involve the abdomen, thus avoiding any possible surgical manipulation of the gastrointestinal tract, and for the severity of the postoperative pain. Pectus excavatum is one of the most common congenital anomalies, occurring more commonly in Caucasian males. A new minimally invasive procedure to repair pectus excavatum was reported by Nuss in 1998 (12), which consists in placing a preformed convex steel bar under the sternum through bilateral thoracic incisions and then forcibly turning the bar over to elevate the sternum. The Nuss procedure is associated with shorter operative time, smaller incisions, less dissection, and negligible blood loss compared with the traditional Ravitch (16) procedure. However, the initial postoperative time is characterized by severe pain, which usually requires a prolonged use of epidural catheters followed by long-term administration of IV and oral narcotics.

The number of dermatomes involved in the Nuss procedure ranges from T1 to T10, and morphine would be the opioid of choice for epidural analgesia in these patients. However, the incidence of side effects after epidural morphine is such that its routine use is problematic with respect to patients' overall comfort. Fentanyl and clonidine are valid alternatives to morphine. We chose a large concentration of fentanyl in the BF group (5 µg/mL) based on the severe level of pain observed after the Nuss procedure and compared it with clonidine and a combination of clonidine and smaller concentration fentanyl. We found that the incidence of vomiting and pruritus was significantly less in patients who received epidural clonidine compared with those who received fentanyl. The infusion of a smaller dose of fentanyl in the BCF group improved the incidence of pruritus and vomiting compared with what was observed in the BF patients. However, their incidence was still frequent enough to possibly have a significant impact on patient satisfaction. Several studies have been conducted in adults to examine patients' preferences for outcomes in the postoperative period. Although using different methods of measuring the risk-benefit relationship, including willingness to pay or rating virtual scenarios (17–19), investigators found that avoiding vomiting is the major priority for adults. In a recent study, Cucchiaro et al. (20) used standard gamble techniques to assess children's preferences with respect to postoperative vomiting and pain management. They found that nausea and vomiting are adverse outcomes of major concern in children. Patients' gender and previous experience with vomiting significantly affected how they compared pain and the side effects of analgesics. It is impossible to determine from our study whether reducing the amount of fentanyl in an epidural infusion has a significant impact on the incidence of postoperative vomiting. Although data on vomiting show a trend towards a clinical significance when comparing patients in the BC and those in the BCF groups, the results were inconclusive because of the small number of patients enrolled and a lower power (0.605) than originally calculated.

Concerns have been raised in the past about the safety and efficacy of epidural clonidine. Several studies conducted in women in labor have shown that boluses of epidural clonidine at doses larger than 100 µg may cause significant sedation (21,22). However, the continuous infusion of clonidine at doses ranging between 0 and 20 µg/h in combination with local anesthetics has been shown to have similar sedative effects to epidural fentanyl (13). Marked sedation has been reported in children aged 3–98 months who were administered 2 µg/kg epidural clonidine, the same dose used in our study, and received a continuous infusion at doses significantly smaller than those used in this study (0.2 µg · kg^–1 · h^–1) (23). The incidence of sedation in our study was minimal and similar among the three study groups. The difference between our data and previous reports may have been a result of the smaller doses of clonidine we used to fill and infuse the epidural catheter and the older age of patients we enrolled in the study.

Epidural clonidine has been shown to produce hypotension, which has been reported with infusion doses ranging between 20 and 40 µg/h (24,25). We used smaller doses of clonidine in our study, and this may explain why only one patient developed significant hypotension during the study period. The incidence of hypotension in the intraoperative and postoperative period was similar in the three study groups, and a similar number of patients required ephedrine during surgery or fluid boluses in the postoperative period. The frequent incidence of episodes of hypotension in the intraoperative period was probably related to the complete sympathectomy caused by the large doses of local anesthetic used to fill the thoracic epidural catheter.

The quality of analgesia obtained in the three study groups was similar, as shown by similar VAS scores. Patients had two options to obtain additional pain medications in addition to the continuous epidural infusion of the study drugs: 1) IV nalbuphine automatically administered by the nursing staff for reported pain scores >3, and 2) additional epidural study medications using the PCEA device. The doses of nalbuphine and the additional amount of study medication used with the PCEA device were similar in the three groups.

In conclusion, this study shows that it is possible to significantly reduce the incidence of side effects caused by epidural narcotics by replacing fentanyl with clonidine. Also, epidural clonidine has the same safety and analgesic efficacy as epidural fentanyl when combined with a local anesthetic. Future study should focus on confirming whether these findings have a significant impact on children's overall satisfaction with their postoperative care.

	APPENDIX 1

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX 1 REFERENCES

 
De Kock sedation scale:

1 = Patient somnolent but responding to verbal commands.

2 = Patient somnolent, nonresponding to verbal commands, but responding to manual stimulation.

3 = Patient somnolent, nonresponding to verbal or manual stimulation.

	Footnotes

 
Accepted for publication February 27, 2006.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION APPENDIX 1 REFERENCES

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Cucchiaro, G. Articles by Watcha, M. Search for Related Content PubMed PubMed Citation Articles by Cucchiaro, G. Articles by Watcha, M. Related Collections Pediatrics Regional Anesthesia Pharmacology