British Journal of Anaesthesia 1991; 67: 559-564

KETAMINE FOR CAUDAL ANALGESIA IN CHILDREN: COMPARISON WITH CAUDAL BUPIVACAINE M. NAGUIB, A. M. Y. SHARIF, M. SERAJ, M. EL GAMMAL AND A. A. DAWLATLY

Caudal analgesia with bupivacaine is used commonly for pain relief in children [1]. More recently, the use of caudal morphine has been extended to children and has also been demonstrated to result in good analgesia [2], but has been associated with side effects, in particular, delayed respiratory depression [2, 3]. Ketamine has analgesic properties which are mediated by different mechanisms. Analgesia after periaqueductal administration of ketamine and its antagonism by naloxone suggested an opioid mechanism of analgesia [4]. This was disputed by Tung and Yaksh, who found that analgesia was reversed by methysergide but not by naloxone, suggesting a serotonergic mechanism [5]. Further, it has been shown that ketamine and phencyclidine selectively reduced responses of

PATIENTS AND METHODS

Institutional Review Board approval and informed consent from parents or guardians were obtained. We studied 50 boys, ASA physical status I, undergoing unilateral inguinal herniotomy. Patients were excluded from the study if a history of allergic reactions to local anaesthetics,

MOHAMED NAGUIB, M.B., B.CH., M.SC., F.F.A.R.C.S.I., M.D.,

Department of Critical Care Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates. AHMED M. Y. SHARIF, M.B., B.CH., D.A., F.F.A.R.C.S.I.; MOHAMED SERAJ, M.B., B.CH., D.A., F.P.A.R.C.S.I.; MOHAMED E L GAMMAL, FACHARZT; ABDEL AZIM DAWLATLY, M.B., B.CH., M.SC., M.D. ; Department

of Anaesthesia, King Khalid University Hospital, Saudi Arabia. Accepted for Publication: April 9, 1991.

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central neurones to N-methyl-aspartate [6], but this effect is not known to mediate analgesia. Animal experiments [7] showed that intrathecal Fifty children undergoing inguinal herniotomy were allocated randomly to three groups to administration of ketamine preserved with receive a caudal injection of either 0.25% bupiv- benzethonium chloride was not associated with acaine 1 ml kg'1 with or without ketamine evidence of macroscopic or microscopic abnor0.5 mg kg'1 or ketamine 0.5 mg kg'1 with normal malities in the spinal cord. Ketamine produces saline 1 ml kg'1. There was no significant dif- potent analgesia [8] without respiratory depresference in quality of pain relief, postoperative sion [9] and would therefore seem to be a suitable behaviour or analgesic requirements between drug for pain relief. Extradural administration of the ketamine group and the two other groups. ketamine has been studied by several investigators The bupivacaine-ketamine mixture provided bet- [10, 11] as an alternative to local analgesics and ter analgesia than the bupivacaine solution alone. opioids, which are not ideal by virtue of their Side effects such as motor weakness or urinary unwanted side effects [2, 3, 12, 13]. Extradural retention were not observed in the ketamine ketamine seemed to be a potent and safe method for postoperative analgesia in adults [10, 11]. group. This double-blind study was designed to compare the analgesic effectiveness of caudal adKEY WORDS ministration of ketamine, bupivacaine or a mixAnalgesia: paediatric, postoperative. Analgesics: ketamine. ture of both drugs in the treatment of pain after Anaesthetic techniques: caudal. Anaesthetics, local: bupivacaine. herniotomy in children. SUMMARY

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BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patient data and duration of surgery {median (range or SE median))

Bupivacaine group (n = 20) Age (months) Weight (kg) Duration of surgery (min)

36 (24-84) 14.6(0.9) 30 (4.3)

42(20-72) 15(0.7) 30 (5.7)

Ketamine group (n •= 15) 36(24-72) 16(0.3) 40 (2.8)

pain; severe pain) and demeanour was scored similarly (cheerful and calm; restless; tense or tearful). Side effects were recorded by the observer in addition to the time at which analgesia, if any, was first received (recovery-analgesia time), and the total number of analgesic doses required in the first 24 h after operation. The patient's ability to stand unaided was assessed 6 h after operation. Postoperative analgesia (paracetamol suppository 125 mg) was prescribed for each patient and was given as required at the discretion of the nursing staff, who were unaware of the group allocation of the patients. Further assessment 24 h after operation was made by nurses and mothers. They were asked to assess the child's behaviour at bed time on the day of operation and on the following morning, with respect to pain and quality of overnight sleep. Data processing

All statistical analyses were carried out using BMDP (1990) statistical package (University of California Press). Kruskal—Wallis test with multiple comparisons was used for comparisons between the groups. In multiple comparisons the null hypothesis was rejected if Z stat is larger than the critical value ZC: where 4> = cumulative standard normal distribution function, a = desired overall significance level, and K = number of groups compared. The times at which analgesia was given were treated as being analogous to survival data. "Survival" curves were plotted to indicate the proportion of patients in each group who had received no analgesia by a given time after operation. The times at which analgesia was first received for the three groups were compared using four non-parametric linear rank tests: The Mantel-Cox (log-rank), Tarone-Ware, Breslow, and Peto-Prentice statistics. These tests compare the observed rate at which patients needed

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bleeding diathesis, aspirin ingestion in the preceding week, or pre-existing neurological or spinal disease were present. No premedication was given and all operations were carried out under general anaesthesia, induced with thiopentone 5-6 mg kg"1 i.v. or with inhalation of nitrous oxide and halothane in oxygen. In all patients, anaesthesia was maintained with 70 % nitrous oxide and halothane in oxygen delivered via an Ayre's T-piece with spontaneous ventilation. No intraoperative sedatives or opioids were administered. After induction of general anaesthesia, patients were allocated randomly to one of three groups. Children in group I received a caudal injection of plain 0.25% bupivacaine lml kg"1. Group II received an identical local anaesthetic dosage mixed with ketamine O.Smgkg"1 and group III received caudal ketamine 0.5mgkg"x in 0.9% sodium chloride using the same weight-related volumes. All blocks were performed by one investigator with the patient in the left lateral position, using a 23-gauge needle under sterile conditions. Ketamine with benzethonium chloride as the preservative was used. A small Elastoplast dressing was placed over the site of sacral hiatus in all patients. After administration of the caudal block, heart rate and pulse oximetry were monitored continuously and arterial pressure was monitored every 5 min by an electronic oscillotonometer. After operation the duration of surgery was noted and the patient was transferred to the recovery room. All patients were observed for 2 h in the recovery room before returning to the ward. When the child was awake, objective pain assessments, ventilatory frequency, arterial pressure and heart rate were recorded by one investigator unaware of the treatment given. Assessments were made at 15-min intervals for the first 1 h, 30-min intervals for the next 1 h and 3, 4, 6 and 24 h after recovery from anaesthesia. The observer scored pain on each occasion with reference to a threepoint scale (none/insignificant pain; moderate

Bupivacaine-ketamine group (n = 15)

CAUDAL KETAMINE FOR POSTOPERATIVE ANALGESIA

561

differ from the two other groups (fig. 1). Caudal administration of bupivacaine with the addition of ketamine resulted in superior analgesia compared with caudal injection of bupivacaine alone. Significantly fewer patients in the latter group had no or insignificant pain at 60 min after recovery from anaesthesia (fig. 1). In addition, the bupiva n q acaine group received significantly more doses of paracetamol than the bupivacaine-ketamine Ketamine group in order to maintain analgesia in the first 100-i n 24 h after recovery from anaesthesia (table II). 80 a. The times at which analgesia was first given are 60 displayed in the form of survival curves in figure 40 2. The curves indicate the proportion of patients 20 who received no analgesia by a given elapsed time 1 I 0 after recovery from anaesthesia. Recoveryanalgesia times were significantly longer in the Bupivacaine 100 bupivacaine-ketamine group than in the bupiv80 acaine group. 60 There was no significant difference between the 40 caudal ketamine group compared with the two 20 other groups in time to first analgesia and the 0 number of analgesic doses required in the first 4 6 24 15 30 45 60 90 2 24 h. (h) (min) Administration of ketamine caudally either Time alone or in combination with bupivacaine was not FIG. 1. Incidence of postoperative pain in the first 24 h after associated with changes in postoperative behavrecovery from anaesthesia. • = None/insignificant pain; 0 = moderate pain; • = severe pain. * P < 0.05 vs caudal iour. Significantly more patients who had received bupivacaine group. caudal ketamine either alone or with bupivacaine were described as cheerful and calm 60 and 90 min after recovery from anaesthesia (fig. 3) analgesia with the rate which might be expected if compared with those in the bupivacaine group. caudal administration of bupivacaine, bupivThe results from mothers' and nurses' assessacaine-ketamine and ketamine were equally effecments 24 h after operation showed no significant tive. P < 0.05 was regarded as statistically signifidifference between the three groups with respect cant. to pain and quality of overnight sleep. Vomiting occurred after operation infive(25 %), four (27 %) RESULTS and two (13 %) patients in the caudal bupivacaine, The groups were comparable in age, weight and bupivacaine-ketamine and ketamine groups, respectively (ns). duration of their operations (table I). Postoperative urinary retention was noted in The quality of analgesia in the group which had received a caudal injection of ketamine did not two patients in the bupivacaine (10%) and 100 -i 806040 20 0

Bupivacaine-ketamine *

TABLE II. Requirement for analgesia during the first 24 h after operation. Number (%) of patients receiving 0-3 doses of paracetamol suppository 125 mg. *P < 0.05 vs caudal bupivacaine group Patients receiving analgesia Analgesia (No. of doses)

Bupivacaine group (n = 20)

Bupivacaine-ketamine* group (n = 15)

Ketamine group (n = 15)

0 1 2 3

10(50) 6(30) 3(15) 1(5)

14 (93) 1(7) 0 0

12(80) 3(20) 0 0

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L

BRITISH JOURNAL OF ANAESTHESIA

562

Bupivacaine-ketamine

1.000 - i - r - i

Ketamine o 'c o a. a. 0.850

Bupivacaine

0.700

6

9 12 15 Time since recovery (h)

18

21

24

FIG. 2. " Survival" curves for the bupivacaine, bupivacaine-ketamine and ketamine groups. Proportion of patients in each group who had not required any analgesia since recovery from anaesthesia.

bupivacaine-ketamine (13%) groups, 6h after recovery from anaesthesia. Two patients (10 %) in the caudal bupivacaine group and one patient (7%) in the caudal bupivacaine-ketamine group were unable to stand 6 h after operation. In contrast, no patient in the caudal ketamine group had urinary retention or any sign of motor weakness. No child in the first 24 h after operation had a recorded ventilatory frequency less than 12 b.p.m. or showed any significant changes in heart rate and arterial pressure. There were no instances of hypotension, bradycardia, residual paralysis or toxic reactions to bupivacaine or ketamine during or after administration of the caudal blocks.

Bupivacaine-ketamine * *

100 80 60 40 20 0

Ketamine *

-100 g 80 | 60

I 40 £

20

I

0 100 -i 80 60 40 20 0

3

DISCUSSION

Bupivacaine

0

15

30 45 (min)

60 90

2

3

4 (h)

6

24

Time FIG. 3. Behaviour in the first 24 h after recovery from anaesthesia. • = Calm and cheerful; 0 = restless; • = tense or tearful. * P < 0.05 vs caudal bupivacaine group.

There is considerable evidence implicating ketamine in the spinal inhibition of nociceptive transmission [4, 5, 14]. The results of the present study confirm previous reports that extradural administration of ketamine exerts modulatory influences on postoperative pain mechanisms [10, 11]. In this study, caudal administration of ketamine 0.5 mg kg"1 produced postoperative analgesia comparable to that associated with caudal injection of 0.25 % bupivacaine 1 ml kg"1 with or without ketamine.

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0.775 •

o

CAUDAL KETAMINE FOR POSTOPERATIVE ANALGESIA

We conclude that caudal administration of ketamine 0.5 mg kg"1 in children produced satisfactory postoperative analgesia after inguinal herniotomy without respiratory depression or other side effects. The quality of analgesia did not

differ significantly from that associated with caudal injection of 0.25% bupivacaine 1 ml kg"1 with or without ketamine. REFERENCES 1. Arthur DS, McNicol LR. Local anaesthetic techniques in paediatric surgery. British Journal of Anaesthesia 1986; 58: 760-778. 2. Krane EJ, Tyler DC, Jacobsen LE. The dose response of caudal morphine in children. Anesthesiology 1989; 71: 48-52. 3. Krane EJ. Delayed respiratory depression in a child after caudal epidural morphine. Anesthesia and Analgesia 1988; 67: 79-82. 4. Havdala HS, Borison RL, Diamond BI. Ketamine anaesthesia and analgesia: neurochemical differentiation. Anesthesiology 1980; S3: S57. 5. Tung AS, Yaksh TL. Analgesic effect of intrathecal ketamine in the rat. Regional Anesthesia 1981; 6: 91-94. 6. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. British Journal of Pharmacology 1983; 79: 565-575. 7. Brock-Ume JG, Kallichurum S, Mankowitz E, Maharaj RJ, Downing JW. Intrathecal ketamine with preservative—histological effects on spinal nerve root of baboons. South African Medical Journal 1981; 61: 440-441. 8. Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine administered in subdissociative doses. Anesthesia and Analgesia 1971; 50: 452^157. 9. Soliman MG, Brinale GF, Kuster G. Response to hypercapnia under ketamine analgesia. Canadian Anaesthetists Society Journal 1975; 22: 486-494. 10. Islas JA, Astorga J, Loredo M. Epidural ketamine for control of postoperative pain. Anesthesia and Analgesia 1985; 64: 1161-1162. 11. Naguib M, Adu-Gyamfi Y, Absood GM, Farag H, Gyasi HK. Epidural ketamine for postoperative analgesia. Canadian Anaesthetists Society Journal 1986; 33: 16-21. 12. Martin LVH. Postoperative analgesia after circumcision in children. British Journal of Anaesthesia 1982; 54: 1263-1266. 13. Bromage P. Epidural Analgesia. Philadelphia: Saunders, 1978; 272. 14. Collins JG. Effects of ketamine on low intensity tactile sensory input are not dependent upon a spinal site of action. Anesthesia and Analgesia 1986; 65: 1123-1129. 15. Ravat F, Dome R, Baechile JP, Beaulaton A, Lenoir B, Leraj P, Palmier B. Epidural ketamine or morphine for postoperative analgesia. Anesthestology 1987; 66: 819-822. 16. Kawana Y, Sato H, Shimada H, Fuijita N, Ueda Y, Hayashi A, Araki Y. Epidural ketamine for postoperative pain relief after gynecologic operations: a double-blind study and comparison with epidural morphine. Anesthesia and Analgesia 1987; 66: 735-738. 17. Wolf AR, Hughes D, Wade A, Mather A, Mather SJ, Prys-Roberts C. Postoperative analgesia after paediatric orchidopexy: evaluation of a bupivacaine-morphine mixture. British Journal of Anaesthesia 1990; 64: 430-435.

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It was noted in adults that a lesser dose of extradural ketamine (4-8 mg) did not produce significant analgesic effects [15, 16]. This observation was reported earlier by Naguib and colleagues [11], who found that ketamine 10 mg in saline 10 ml administered extradurally was ineffective in producing analgesia and all of the patients in that group required additional doses. In contrast, by increasing the dose of ketamine to 30 mg, 54 % of the patients had adequate analgesia for 24 h after a single extradural injection [11]. Caudal block with bupivacaine alone can provide adequate analgesia in the early postoperative period, but as the block wears off, systemic analgesia is often required [17]. In the present study, 20 % and 50 % of patients in the caudal ketamine and bupivacaine groups, respectively, required additional analgesia during the first 24 h after surgery (table II). These results are similar to those of a previous report on herniotomy [18], in which 55 % of patients who had caudal block with 0.25 % bupivacaine 1 ml kg"1 required further analgesia. The addition of ketamine 0.5 mg kg"1 to bupivacaine improved significantly both quality and duration of analgesia compared with administration of bupivacaine solution alone, without an increase in the incidence of side effects. There was a significant reduction in the amount of postoperative analgesia required by the children in the bupivacaine-ketamine group compared with those receiving bupivacaine alone. In addition, the recovery-analgesia times were significantly shorter in the latter group (fig. 2). The overall incidence of side effects observed in the bupivacaine and bupivacaine-ketamine groups was comparable to that reported previously in children who received caudal bupivacaine [18, 19]. Respiratory depression, urinary retention and pruritis have been described in children after caudal administration of opioids [2, 3, 17], but these side effects were not encountered in this study after caudal injection of ketamine O.Smgkg"1. Caudal ketamine was not associated with motor block, and rapid mobilization was possible in that group.

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564 18. Fell D, Derrington MC, Taylor E, Wandless JC. Paediatric postoperative analgesia. A comparison between caudal block and wound infiltration of local anaesthetic. Anaesthesia 1988; 43: 107-110.

BRITISH JOURNAL OF ANAESTHESIA 19. Wolf AR, Valley RD, Fear DW, Roy WL, Lerman J. Bupivacaine for caudal analgesia in infants and children: the optimal effective concentration. Antsihesiology 1988; 69: 102-106.

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