Comparison of a bupivacaine-clonidine mixture with plain bupivacaine for caudal analgesia in children†

British Journal of Anaesthesia 1994; 72: 258-262

CLINICAL INVESTIGATIONS

Comparison of a bupivacaine-clonidine mixture with plain bupivacaine for caudal analgesia in childrenf J. J. LEE* AND A. P. RUBIN

SUMMARY

KEY WORDS Analgesic techniques: caudal. Anaesthetics, local: bupivacaine. Analgesia: paediatric. Analgesia, postoperative. Sympathetic nervous system: clonidine.

Caudal analgesia is the most popular and commonly used regional block in paediatric surgery [1]. The use of opioids alone or in combination with local anaesthetics has been demonstrated to improve caudal analgesia in children, but has also been associated with side effects, such as nausea and vomiting, pruritus, urinary retention and potentially life-threatening respiratory depression [2-7]. Clonidine, an alpha2 agonist, has been used effectively for the treatment of acute and chronic pain [8]. It has been shown to provide analgesia of variable efficacy and duration [9-13] and to potentiate postoperative analgesia when used in combination with local anaesthetics [14—16] or opioids [17—19], via the extradural and intrathecal routes. Furthermore, clonidine lacks the side effects which are associated with the use of systemic and spinal opioids, but does demonstrate adverse effects including sedation, hypotension and bradycardia [8]. This study was designed to compare the analgesic efficacy and side effects of a bupivacaine-clonidine mixture with plain bupivacaine for caudal analgesia in children.

After obtaining informed written consent from their parents and approval from the local research Ethics Committee, we studied 46 healthy children, aged 1-10 yr, undergoing lower limb orthopaedic surgery. All children received a standard premedication comprising oral trimeprazine 1.5 mg kg"1 at 2 h, followed by morphine 0.2 mg kg"1 i.m. and atropine 0.02 mg kg"1; EMLA cream was applied to both hands 1 h before surgery. Anaesthesia was induced with thiopentone and maintained with 0.5-1.0% enflurane and nitrous oxide in oxygen. Vecuronium was given to facilitate tracheal intubation and ventilation. The children were then allocated randomly, by random number table, to two equal groups to receive caudal analgesia before surgery. Group A received 0.25 % bupivacaine 1 ml kg"1 with normal saline 1 ml and group B received 0.25 % bupivacaine 1 ml kg"1 with clonidine 2 (ig kg"1 in normal saline 1 ml. The caudal mixtures were prepared by another anaesthetist who was not involved in the study and administered in a double-blind manner, with a maximum volume of 0.25 % bupivacaine 30 ml. All caudal blocks were performed by the same investigator, with the patient in the left lateral position and using a 23-gauge needle under aseptic conditions. Intraoperative analgesic supplements were not given. Standard monitoring was used during anaesdiesia and surgery. Perioperative blood loss was replaced meticulously using crystalloids and blood, as appropriate. All patients were admitted routinely to the postoperative (high dependency) ward for at least 12 h and, when fully awake and pain-free, returned to the children's ward. Heart rate and arterial pressure were recorded before operation. After caudal block, these two variables were recorded every 5 min until the end of surgery. We recorded the time from induction of anaesthesia to the end of surgery when the inhalation agent was discontinued, and the time from end of J. J. LEE*, M.B., B.S., D.A., F.F.A.R.C.S.I., A. P. RUBIN, M.B., B.CHIR., L.R.C.P., M.R.C.S., D.A., F.R.C.A., Department of Anaesthesia, Royal

National Orthopaedic Hospital, Brockley Hill, Stanmore HA7 4LP. Accepted for Publication: October 4, 1993. 'Present address: Department of Anaesthesia, The Royal London Hospital, Whitechapel, London El IBB. fThis paper was presented in part to the North East Thames Region Anaesthetists Society Meeting, April 24, 1993.

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In a randomized, double-blind study in children undergoing elective orthopaedic surgery, we have assessed the clinical value of combining clonidine with bupivacaine for caudal analgesia. Forty-six children, aged 1-10 yr, were allocated randomly to two equal groups to receive 0.25% bupivacaine 1 ml kg~' combined with either normal saline 1 ml (group A) or clonidine 2 fig kg'' in normal saline 1 ml (group B). Mean (SD) duration of caudal analgesia for groups A and B were 5.2 (1.2) h and 9.8 (2.1) h, respectively (P < 0.0001). Group B required significantly less supplementary analgesia after operation (P < 0.01). There was no significant difference in the incidence of side effects between the two groups. The longer duration of sedation in group B (9.1 (2.5) h) resulted partly from the sedative effect of clonidine and partly from the longer duration of analgesia provided by clonidine. We conclude that, when added to bupivacaine, clonidine improves the efficacy of caudal analgesia in children. (Br. J. Anaesth. 1994; 72: 258-262)

PATIENTS AND METHODS

BUPIVACAINE-CLONIDINE MIXTURE FOR CAUDAL ANALGESIA

No. of subjects Age (yr) Weight (kg) Duration of general anaesthesia (min) Recovery time (min)

Group B

23 5.8(1.1-10.2) 20.2 (8.2-35.5) 80(50-140)

23 5.6(1.2-10.5) 18.8(10.1-36.8) 86(45-155)

15.5 (8-45)

19.1 (10-50)

TABLE II. Number of patients undergoing different types of operations No. of patients Types of operation

Group A

Group B

Femoral osteotomy Innominate osteotomy Acetabuloplasty Open reduction of hip Correction of club foot Total

12 3 2 3 3 23

11 4 2 4 2 23

TABLE I I I . Number of patients maintaining adequate caudal analgesia without the need for morphine or paracetamol. **P < 0.01 between groups No. of patients ^Jn of hours after surgery

Group A

Group B

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

23 23 23 18 14 8 3 0 0 0 0 0 0 0 0

23 23 23 23 23 23 21 19 14 7 5 4 3 2 0

4. ^ V^ *

VA

llv

ill

O

** •* ** ** ** **

RESULTS

Mean ages, weights and duration of surgery and recovery times were comparable between groups (table I). The number of children who underwent the different types of lower limb operations was also comparable (table II). Mean (SD) duration of caudal analgesia was 5.2 (1.2) h for group A and 9.8 (2.1) h for group B (P < 0.0001). Table III shows the number of patients who maintained adequate caudal analgesia (a pain score of less than 4) without requiring supplementary morphine or paracetamol in the postoperative period. During the first 3 h after operation, all children in both groups had adequate caudal analgesia. Subsequently, the number of patients with adequate analgesia in group A declined much more rapidly than group B and the differences were statistically significant from 5 to 10 h after operation. The total postoperative analgesic requirements for morphine and paracetamol were also significantly less in group B (table IV). Analgesia was not given to any child in the first hour after operation. In group A, four children required morphine by 4 h and all 23 children had required a total of 16 and 18 administrations of morphine and paracetamol, respectively,

surgery to opening the eyes on calling the patient's name (recovery time). The duration of caudal analgesia was defined from the time of caudal injection to the time the child first complained of pain or time of first postoperative analgesic requirement. During the first 24 h after operation, the following variables were recorded: heart rate, arterial pressure, ventilatory frequency, sedation score (1 = alert, 2 =

TABLE IV. Total number of administrations of postoperative supplementary analgesia. **P < 0.01 compared with group B No. of administrations No. of hours after surgery

Morphine

Paracetamol

Morphine

Paracetamol

1 4 12 24

0 4 16** 26**

0 0 18** 40**

0 0 6 16

0 0 7 29

Group A

Group B

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awake but drowsy or 3 = asleep) and objective behavioural pain score. These measurements were made at 15-min intervals for the first 2 h, then hourly for 10 h and then every 2 h for the remaining 12 h. The quality of analgesia was assessed using a pain scoring system modified from Hannallah and colleagues [20] and which was based on five criteria: arterial pressure, crying, movement, agitation and localization of pain. Each criterion was given a score of 0-2, with 2 being the worst, making a total worst possible score of 10. A total score of less than 4 was regarded as an indication of adequate analgesia. Thus the children were given analgesia after operation of either morphine 0.2 mg kg"1 i.m. or oral paracetamol 120-500 mg by the attending staff when they scored 4 or more. Postoperative recordings also included continuous pulse oximetry whilst in the postoperative ward, time of administration of morphine and paracetamol, time to first micturition after caudal injection and the incidence of catheterization and vomiting. Parametric data were compared using Student's t test. The Mann-Whitney U test and chi-square test with Yates' correction were used for nominal and non-parametric data analysis. P < 0.05 was regarded as statistically significant.

TABLE I. Patient and clinical data (mean (range)) Group A

259

BRITISH JOURNAL OF ANAESTHESIA

260 TABLE V. Haemodynamic data {mean (SEM)) Group A MAP (mm Hg) Before op. 81(4) Maximal decrease Magnitude 19.2 (6.3) Time (min) after 44(5) caudal injection Nil Therapy Heart rate (beat min"1) Before op. 103(10) Maximal decrease Magnitude 22(2) Time (min) after 71 (10) caudal injection Nil Therapy

Group B 82(3) 19.6 (8.2) 70(9) Nil

106(13) 19(3) 83(9) Nil

Group A Vomiting (No.) Time to micturition (h) Urinary retention (No.) Duration of sedation (h)

Group B

13

11

8.5(5.1)

8.4 (5.8)

1

5.8(1.5)

0

9.1 (2.5)

within 12 h and 26 and 40 administrations of morphine and paracetamol, respectively, by 24 h. In group B, no analgesia was required within 4 h, but nine children had required a total of 6 and 7 administrations of morphine and paracetamol, respectively, within 12 h and all 23 children a total of 16 and 29 administrations of morphine and paracetamol, respectively, by 24 h. The difference in postoperative analgesic requirements between groups was statistically significant by 12 and 24 h (P < 0.01).

DISCUSSION

Caudal blocks in children with 0.25 % bupivacaine provide between 4 and 8 h of analgesia [1]. There are obvious advantages, especially in children, in prolonging the duration of postoperative analgesia and reducing the frequency of parenteral opioid administration. Hence, recently several studies have re-

TABLE VII. Postoperative sedation score and observed ventilatory frequency (mean (SD)) Intervals after surgery

Sedation score

Ventilatory frequency (b.p. m.)

(h)

Group A

Group B

Group A

Group B

0.25 0.50 0.75

3(0) 3(0) 3(0) 2.7 (0.4) 2.8 (0.3) 2.8 (0.3) 2.7 (0.4) 2.8(0.7) 2.4 (0.6) 2.3 (0.9) 1.7(0.6) 2.2 (0.9) 2.1 (0.8) 2.3 (0.8) 2.4 (0.7) 2.7 (0.5) 2.2 (0.9) 2.7 (0.6) 2.6 (0.7) 1.9(0.6) 1.8(0.6) 1.4(0.8) 1.2(0.6)

3(0) 3(0) 3(0) 3(0) 2.9 (0.2) 2.9 (0.2) 2.9 (0.3) 2.9 (0.4) 2.5 (0.7) 2.3 (0.8) 2.4 (0.6) 2.5 (0.7) 2.3 (0.8) 2.5 (0.6) 2.5 (0.7) 2.6 (0.6) 1.8(0.7) 2.0 (0.8) 2.8 (0.7) 2.0 (0.9) 1.6(0.9) 1.5(0.7) 1.2(0.4)

18(3) 20(2) 19(3) 19(3) 21(3) 21(3) 21(3) 23(2) 21(4) 20(2) 19(2) 16(4) 20(3) 19(1) 21(2) 20(3) 18(3) 18(3) 18(2) 17(2) 16(1) 18(2) 16(2)

17(4) 19(4) 19(4) 19(3) 18(4) 19(5) 20(3) 20(1) 22(3) 21(4) 21(3) 18(4) 21(3) 20(4) 20(3) 20(2) 19(3) 18(1) 18(2) 18(2) 18(2) 19(1) 18(2)

1

1.25 1.5

1.75 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 24

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TABLE VI. Incidence of sideeffects (mean(SD) or No.)

The magnitude of haemodynamic changes between groups was similar (table V). The maximal magnitude of decrease in mean arterial pressure (MAP) was 19.2 mm Hg for group A and 19.6 mm Hg for group B and occurred at mean times of 44 and 70 min, respectively, after caudal injection. The maximal magnitude of decrease in heart rate was 22 beat min"1 for group A and 19 beat min"1 for group B and occurred at mean times of 71 and 83 min, respectively, after caudal injection. Therapeutic interventions were not required. The incidence of vomiting was comparable between groups (table VI). Mean times to first micturition were 8.5 and 8.4 h for groups A and B, respectively. One child in group A required catheterization and two children in group B complained of difficulty with micturition but did not require catheterization. Mean duration of sedation in the immediate postoperative period and before supplementary analgesia was required were 5.8 and 9.1 h for groups A and B, respectively (table VI). These durations of sedation were very similar to the respective durations of caudal analgesia. None of the children had either an SpO2 value of less than 95% or ventilatory frequency less than 16 b.p.m. throughout the postoperative period. Sedation scores and observed ventilatory frequencies recorded at the stated intervals after surgery are shown in table VII.

BUPIVACAINE-CLONIDINE MIXTURE FOR CAUDAL ANALGESIA

Visconi [9], in a dose-response study, demonstrated that extradural clonidine, administered in doses ranging from 100 to 900 ug, produced a dosedependent increase in analgesic effects and associated side effects and in addition, complete analgesia when clonidine 700 ug or more was used in adults. However, smaller doses of extradural clonidine, such as 1 to 2 ug/kg body weight or 150 ug, have been used in adult patients to provide satisfactory postoperative analgesia [10,11,27], especially when combined with a local anaesthetic [16] or opioid [17, 19], with an acceptable incidence of side effects. The addition of clonidine to bupivacaine in our study did not result in an increase in the incidence of side effects. The 70-min time of maximal decrease in MAP in group B may occur during the postoperative period, and if the patient is moved, this may lead to a further reduction in MAP. Hence closer monitoring is required for this group during the postoperative period. The period of sedation was significantly longer in children who received clondine. However, it is difficult to distinguish between sedation and analgesia, as we noticed that all our subjects were asleep provided they were comfortable and they became restless or awake only when they were in pain and required analgesia. The greater analgesic effect of clonidine might be mistaken for sedation and vice versa. Hence we cannot conclude reliably that the longer duration of sedation was caused entirely by the sedative effect of clonidine. Moreover, the addition of clonidine did not delay significantly recovery from general anaesthesia. There were no detectable differences in oxygen saturation or ventilatory frequency between the groups. Few studies have investigated the ventilatory effects of clonidine and the results have been conflicting. Oral clonidine, in doses ranging from 3.5 to 5 ug kg"1, was given to volunteers with or without co-administration of morphine [28] or alfentanil [29]. Hypercapnic ventilatory responses revealed that clonidine alone produced little respiratory depression and did not potentiate opioid-induced respiratory depression. Narchi and colleagues [30] confirmed the lack of significant respiratory depression with extradural clonidine 150 ug after Caesarean section, but the use of 300 ug was associated frequently with marked sedation, obstructive apnoea and arterial oxygen desaturation. Penon, Ecoffey and Cohen [31] also reported that clonidine 300 ug, administered extradurally, decreased the slope of ventilatory response to carbon dioxide, resulting in mild respiratory depression. Nevertheless, the dose of clonidine used in our study was much smaller and the consequent risk of respiratory depression would be minimal. ACKNOWLEDGEMENTS We thank Mr A. J. Catterall and Dr K. Yau and all nursing staff involved for their help and support, and Boehringer Ingelheim Ltd for their voluntary supply of clonidine. REFERENCES 1. Lloyd-Thomas AR. Pain management in paediatric patients. British Journal of Anaesthesia 1990; 64: 85-104.

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ported caudal use of opioids and other drugs in children to improve postoperative analgesia. Caudal morphine in doses varying from 0.033 to 0.1 mg kg"1 and with or without plain bupivacaine, has been studied by several investigators [2-6] who reported a dose-dependent increase in duration of analgesia of up to 36 h. However, side effects, including pruritus, urinary retention, nausea and vomiting, were common. Excessive sedation has also been reported [5]. Furthermore, a case of delayed and severe respiratory depression was reported in a 2.5-year-old child 3.5 h after receiving caudal morphine 0.1 mg kg"1 [7]. In a retrospective study of 138 paediatric patients who received caudal morphine 0.07 mg kg"1, Valley and Bailey [5] reported 11 cases of respiratory depression, 10 of which occurred in infants aged 12 months or younger, and who had also received parenteral opioids. In general, fear of potentially life-threatening respiratory complications has limited the widespread use of morphine via the caudal route in children. Other drugs which have been used for caudal analgesia in paediatric patients are buprenorphine [21], ketamine [22] and adrenaline 1:200000 [23], all of which were shown to provide significantly improved analgesia without any increase in the incidence of side effects, apart from excessive sedation associated with buprenorphine. However, fentanyl has not been shown to offer advantages over conventional caudal analgesia with bupivacaine [24]. Jamali and co-workers [25] have recently conducted a preliminary investigation of the use of clonidine in paediatric caudal anaesthesia using 0.25 % bupivacaine 1 ml kg"1 mixed with clonidine 1 ug kg"1 or adrenaline 5 ug ml"1. The quality of analgesia was better in the clonidine group with mean duration of analgesia of 16.8 h and 4.7 h for the clonidine and adrenaline groups, respectively. Systolic arterial pressure in the clonidine group was also reported to be significantly reduced over the first 2 h, with a mean maximal decrease of 6.5 % at 1 h, which is consistent with the time of maximal decrease of MAP at 70 min in our study. Bradycardia and respiratory depression were not noticed. However, the type of surgery performed was not reported and the incidence of other side effects, such as nausea and vomiting, urinary retention and sedation was not recorded. We have shown that the addition of clonidine 2 ug kg"1 to 0.25 % bupivacaine 1 ml kg"1 significantly improved caudal analgesia compared with that provided by bupivacaine alone, without an increase in the incidence of side effects, in children undergoing orthopaedic surgery. However, the duration of analgesia was considerably shorter than that reported by Jamali and colleagues [25] for the clonidine group, despite the administration of twice the amount of clonidine in our study. This is perhaps not surprising, albeit disappointing, as clonidine is known to provide analgesia of variable intensity and duration, as reported in other studies [9-13]. Extradural clonidine has been demonstrated to produce regional analgesia by a local, spinal action on alpha2 adrenergic receptors located on the dorsal horn of the spinal cord [26]. Eisenach, Lysak and

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