Caudal blockade is the most popular regional anesthetic technique used in children (1). Bupivacaine is the local anesthetic with the longest duration of action currently available, and when used for caudal analgesia in children in a dose of 2.0–2.5 mg/kg, it lasts for 2–4 h. More than 60% of children undergoing orchidopexy with this technique require further analgesia during the postoperative period (2). Many drugs including epinephrine (3), morphine (4), clonidine (3), ketamine (3,4), midazolam (5), and tramadol (6,7) have been co-administered with caudal bupivacaine to maximize and extend the duration of analgesia. Caudal morphine extends postoperative analgesia, but it may be associated with delayed respiratory depression (8). Caudal clonidine and midazolam have been associated with prolonged sedation (5,9). Behavioral side effects were reported with the use of the caudal ketamine (10), and an increased incidence of postoperative vomiting was observed with the use of caudal tramadol (6,7).
The intrathecal administration of the cholinesterase inhibitor neostigmine was reported to produce analgesia in experimental animals (11) and in acute postoperative pain in humans (12). Two reports have described the use of epidural neostigmine combined with local anesthetics or morphine in the management of acute postoperative and chronic cancer pain in adults (13,14). The use of neuraxial neostigmine has not been reported before in children.
This double-blinded, randomized study was designed to compare the analgesic efficacy of caudal administration of neostigmine, bupivacaine, or a mixture of both in the management of postoperative pain after hypospadias repair in children.
The local ethics and research committee approved the study, and informed consent from parents was obtained. We studied 60 boys, ASA physical status I, aged 2–10 yr old, undergoing hypospadias repair surgery. Patients with a history of allergic reactions to local anesthetics, bleeding diathesis, aspirin ingestion in the preceding week, or preexisting neurological or spinal diseases were excluded from the study.
No premedication was given, and general anesthesia was induced with nitrous oxide, oxygen, and halothane. After endotracheal intubation, anesthesia was maintained with 70% nitrous oxide in oxygen and halothane 0.5%–2.5% delivered via an Ayre’s T-piece with spontaneous ventilation. No intraoperative muscle relaxants, sedatives, or opioids were administered, and the inspired halothane concentration was adjusted to maintain the heart rate at ± 20% of the baseline preinduction values. Inspired halothane concentration was recorded every 5 min, and the average intraoperative halothane concentration was determined for all patients.
After the induction, a peripheral IV line was secured, and Dextrose 5% in 0.45 NaCl was infused at a rate of 4–6 mL · kg−1 · h−1. Caudal block was performed with the patient in the left lateral position using a 23-gauge short-beveled needle under sterile conditions. Patients were allocated randomly into one of three equal groups (n = 20) by a computer-generated randomization scheme. Children in Group 1 received a caudal injection of 0.25% bupivacaine 1 mL/kg. Patients in Group 2 received an identical local anesthetic dosage mixed with neostigmine 2 μg/kg. Group 3 received caudal neostigmine 2 μg/kg diluted in 0.9 NaCl solution to a total volume of 1 mL/kg. The neostigmine preparation used in this study included methylparaben and propylparaben as preservatives (Gensia, Inc, San Diego, CA). Surgical intervention started 10–15 min after the caudal injection of the analgesic medication.
Heart rate and pulse oximetry were monitored continuously, and arterial blood pressure was monitored every 5 min by an electronic oscillometer. After the operation was completed, the duration of surgery was noted, and patients were transferred to the recovery room. The time between the discontinuation of anesthesia to spontaneous eye opening was recorded (recovery time). All patients were observed for 2 h in the recovery room before returning to the ward. When the child was awake in the recovery room, one investigator, unaware of the caudal analgesic treatment given, recorded ventilatory frequency, arterial blood pressure, and heart rate. Postoperative pain was assessed using an objective pain score (2). This score uses five criteria: crying, agitation, movement, posture, and localization of pain. Each criterion scores from 0–2 to give a possible total score of 0–10. A postoperative pain score of ≥ 4 was managed with paracetamol 15 mg/kg by mouth every 4 h as required. The time at which postoperative rescue analgesia, if any, was first received (recovery-analgesia time) and the number of paracetamol doses per 24 postoperative h were noted. Assessments were made at 30-min intervals for the first 2 h and at 4, 6, 8, 12, and 24 h after recovery from anesthesia.
Side effects were recorded, and the patient’s ability to stand unaided was assessed 6 h after the operation. Assessments of the level of sedation were made at 1 and 4 postoperative h using an objective score based on eye opening (eyes open spontaneously = 0, eyes open in response to speech = 1, and eyes open in response to physical stimulation = 2) (10).
Statistical analyses were performed using analysis of variance, Kruskal-Wallis test, and Fisher’s exact test, as appropriate. P value <0.05 was considered significant.
Patient characteristics and duration of surgery were comparable in the three study groups. The mean ± sd age, weight, and duration of surgery in the bupivacaine/neostigmine, bupivacaine, and neostigmine groups were, respectively, 2.8 ± 1.3 yr, 2.7 ± 1.4 yr, and 3.1 ± 1.2 yr, 12.9 ± 3.1 kg, 12.6 ± 2.6 kg, and 14.1 ± 1.4 kg, and 81.2 ± 21.8 min, 75.5 ± 22.2 min, and 74 ± 19.7 min. The average inspired intraoperative halothane concentration in the caudal neostigmine group was 1.6% ± 0.4% and was significantly larger than the bupivacaine/neostigmine group (0.6% ± 0.2%) and the bupivacaine group (0.55% ± 0.2%;P < 0.05). Intraoperative heart rate was significantly increased in the caudal neostigmine group compared with the bupivacaine/neostigmine and the bupivacaine groups. The time to spontaneous eye opening after anesthesia was 24.2 ± 6.9 min in the caudal neostigmine group and was significantly longer than the bupivacaine/neostigmine (12.4 ± 5.6 min) and bupivacaine (14.1 ± 4.3 min) groups (P < 0.01).
Caudal administration of bupivacaine with the addition of neostigmine resulted in superior analgesia compared with the other two groups. Recovery to first analgesic times were 22.8 ± 2.9 h, 8.1 ± 5.9 h, and 5.2 ± 2.1 h, respectively, in the bupivacaine/neostigmine, bupivacaine, and neostigmine groups (P < 0.001;Fig. 1). In addition, the bupivacaine and neostigmine groups received more doses of paracetamol than the bupivacaine/neostigmine group to maintain adequate analgesia in the first 24 postoperative h (Table 1).
Vomiting occurred in the recovery room in 5 (25%), 2 (10%), and 6 (30%) patients in the caudal bupivacaine/neostigmine, bupivacaine, and neostigmine groups, respectively (P < 0.01). Postoperative vomiting was not severe or repeated and was effectively managed with a single dose of IV ondansetron 0.1 mg/kg. Oral intake and discharge from the hospital were not delayed. All children in the three study groups were able to stand unassisted at the sixth postoperative h. No child had a recorded respiratory rate of <15 breathes/min or showed any significant changes in heart rate and blood pressure in the first 24 postoperative h. There were no instances of postoperative sedation, hypotension, bradycardia, or pruritus.
The present study demonstrated that caudal neostigmine in a dose of 2 μg/kg co-administered with 1 mL/kg of bupivacaine 0.25% markedly prolonged postoperative analgesia and reduced the need for oral paracetamol in children undergoing hypospadias surgery. Caudal neostigmine is effective as a sole analgesic with a duration of analgesia comparable to that reported with caudal bupivacaine 0.25%(2). In line with the findings of the present study, co-administration of neostigmine with epidural lidocaine in adults significantly extended the duration of postoperative analgesia (13).
The analgesic effects of caudal neostigmine observed in the present study may be attributed either to the direct action at the spinal cord level after transdural diffusion to the cerebrospinal fluid (CSF) or a peripheral antinociceptive effect at the surgical site after systemic absorption. Intrathecal neostigmine causes analgesic effects in humans by inhibiting the breakdown of the acetylcholine in the dorsal horn of the spinal cord (15). Spinal muscarinic M1 receptors are believed to be involved in the analgesic properties of spinal neostigmine (16). Studies also support the hypothesis of a peripheral antinociceptive effect of neostigmine (17). The dose required to achieve analgesia after peripheral administration of neostigmine, e.g., intraarticular injection, is approximately 10–100 times its analgesic neuraxial dose (500 μg peripheral versus 5–50 μg spinal or epidural) (13,17). The effectiveness of the small dose of caudal neostigmine (2 μg/kg) used in the present study suggests a spinal rather than a peripheral mechanism of action. A future pharmacokinetic evaluation of serum and CSF concentrations of neostigmine after its epidural administration is required to confirm a neuraxial site of action.
A potential advantage of subarachnoid neostigmine is that it may counteract local anesthetic and clonidine-induced hypotension and tends to increase the respiratory rate (18,19). The addition of neostigmine has been demonstrated to effectively counteract the inhibitory effect of spinal bupivacaine on the sympathetic nerve activity (20). The perioperative hemodynamic stability observed with the use of the caudal bupivacaine/neostigmine mixture in the present study supports this contention. The relatively faster intraoperative heart rate and increased halothane requirements recorded in the caudal neostigmine group can be attributed to the elimination of the local anesthetic component from the caudal analgesic mixture and a consequent lack of sensory block in this group. The favorable hemodynamic and respiratory profile of neuraxial neostigmine makes this drug an attractive alternative to the currently used epidural antinociceptive drugs.
The dose of caudal neostigmine used in the present study was chosen in view of the epidural neostigmine study in adults. Lauretti et al. (13) hypothesized that the analgesia mediated by epidural neostigmine is caused by the drug spread into the CSF at approximately one tenth of the initial epidural dose administered. Neostigmine is a hydrophilic molecule similar to morphine. Only 10%–20% of an extradural dose of morphine crosses the dura into the CSF. This is reflected in the larger doses used by the epidural route (10 mg of extradural morphine daily is equivalent to 1 mg daily of intrathecal morphine) (21). Lauretti et al. (13) translated morphine data to the preliminary choice of potentially effective epidural neostigmine dose levels in adults. By simple calculations, they concluded that an intrathecal neostigmine dose of 10 μg would be somewhat related to 100-μg dose of epidural neostigmine (2 μg/kg for a 50-kg patient).
Neostigmine preparations used in the present study included methyl- and propylparabens as preservatives. Early experimental and clinical trials used preservative-free neostigmine (11,12). Although preservative-free neostigmine is not associated with neurotoxicity (22), it is no longer marketed. Two investigations have confirmed that chronically administered intrathecal neostigmine containing methyl- and propylparabens is not associated with any behavioral, chemical, or histopathological evidence of neurotoxicity (23,24).
Despite its proven analgesic effectiveness, neuraxial neostigmine is not yet a widely accepted analgesic modality in clinical practice and continues to be an off-label indication. This is mainly because of the frequent incidence of nausea and vomiting (12). In a dose-response study, an intrathecal neostigmine dose range of 6.25–50 μg was associated with a relatively frequent incidence of nausea (33%–67%) and vomiting (17%–50%) (25). Reducing the dose to 10 μg, the addition of 5% dextrose solutions, and the head-up position in patients receiving spinal neostigmine are effective measures in reducing the incidence of nausea and vomiting (18,26). The only available clinical trial describing the use of epidural neostigmine in adults had reported an infrequent incidence of nausea and vomiting (13). Probably the epidural route of administration of neostigmine may eventually prove superior to the intrathecal route with respect to the incidence of associated nausea and vomiting. In the present study, the incidence of vomiting with the use of caudal bupivacaine/neostigmine and neostigmine was 25% and 30%, respectively. A similar incidence of postoperative vomiting was reported with the use of caudal bupivacaine/epinephrine combination in children aged two to six years old undergoing repair of inguinal hernias (27). In the aforementioned study, substitution of caudal block with IV ketorolac tromethamine reduced the incidence of postoperative vomiting (incidence of vomiting was 29% and 15% in the caudal block and the ketorolac groups, respectively) (27). Future clinical research is required to identify the minimally effective caudal neostigmine dose that has analgesic efficacy and minimal or no side effects.
In conclusion, caudal neostigmine 2 μg/kg provides postoperative analgesia comparable to 1 mL/kg of caudal bupivacaine 0.25% in children undergoing hypospadias repair surgery. Co-administration of the two drugs is associated with extended duration of postoperative analgesia and reduced need for supplementary analgesics.
1. Markakis DA. Regional anesthesia in pediatrics. Anesthesiol Clin North America 2000; 18: 355–81.
2. Wolf AR, Hughes D, Wade A, et al. Postoperative analgesia after paediatric orchidopexy: evaluation of a bupivacaine-morphine mixture. Br J Anaesth 1990; 64: 430–5.
3. Cook B, Grubb DJ, Aldridge LA, Doyle E. Comparison of the effects of adrenaline, clonidine, and ketamine on the duration of caudal analgesia produced by bupivacaine in children. Br J Anaesth 1995; 75: 698–701.
4. Naguib M, Sharif AM, Seraj M, et al. Ketamine for caudal analgesia in children: comparison with caudal bupivacaine. Br J Anaesth 1991; 67: 559–64.
5. Naguib M, El-Gammal M, Yasser S, et al. Midazolam for caudal analgesia in children: comparison with caudal bupivacaine. Can J Anaesth 1995; 42: 758–64.
6. Gunduz M, Ozcengiz D, Ozbek H, Isik G. A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children. Paediatr Anaesth 2001; 11: 323–6.
7. Batra YK, Prasad MK, Arya VK, et al. Comparison of caudal tramadol vs bupivacaine for post-operative analgesia in children undergoing hypospadias surgery. Int J Clin Pharmacol Ther 1999; 37: 238–42.
8. Krane EJ. Delayed respiratory depression in a child after caudal epidural morphine. Anesth Analg 1988; 67: 79–82.
9. Lee JJ, Rubin AP. Comparison of a bupivacaine clonidine mixture with plain bupivacaine for caudal analgesia in children. Br J Anaesth 1994; 72: 258–62.
10. Semple D, Findlow D, Aldridge LM, Doyle E. The optimal dose of ketamine for caudal epidural blockade in children. Anaesthesia 1996; 51: 1170–2.
11. Hood DD, Eisenach JC, Tong C, et al. Cardiorespiratory and spinal cord blood flow effects of intrathecal neostigmine methyl sulphate, clonidine, and their combination in sheep. Anesthesiology 1995; 82: 428–35.
12. Lauretti GR, Reis MP, Prado WA, Klamt JG. Dose-response study of intrathecal morphine vs intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg 1996; 82: 1182–7.
13. Lauretti GR, Oliveira R, Reis MP, et al. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999; 90: 1534–40.
14. Lauretti GR, Gomes JM, Reis MP, Pereira NL. Low doses of epidural ketamine or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anesth 1999; 11: 663–8.
15. Shafer SL, Eisenach JC, Hood DD, Tong C. Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1998; 89: 1074–88.
16. Naguib M, Yaksh TL. Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord. Anesth Analg 1997; 85: 847–53.
17. Yang LC, Chen LM, Wang CJ, Buerkle H. Postoperative analgesia by intra-articular neostigmine in patients undergoing knee arthroscopy. Anesthesiology 1998; 88: 334–9.
18. Krukowski JA, Hood DD, Eisenach JC, et al. Intrathecal neostigmine for postcesarean section analgesia: dose response. Anesth Analg 1997; 84: 1269–75.
19. Williams JL, Tong C, Eisenach JC. Neostigmine counteracts spinal clonidine-induced hypotension in sheep. Anesthesiology 1993; 78: 301–6.
20. Pan HL, Song H, Eisenach JC. Effects of intrathecal neostigmine, bupivacaine, and their combination on sympathetic nerve activity in rats. Anesthesiology 1998; 88: 481–6.
21. Watson PJK, Moore RA, McQuay HJ. Plasma morphine concentration and analgesic effects of lumbar extradural morphine and heroin. Anesth Analg 1984; 63: 529–34.
22. Yaksh TL, Grafe MR, Malkmus S, et al. Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology 1995; 82: 412–27.
23. Gurun MS, Leinbach R, Moore L, et al. Studies on the safety of glucose and paraben-containing neostigmine for intrathecal administration. Anesth Analg 1997; 85: 317–23.
24. Eisenach JC, Hood DD, Curry R. Phase I human safety assessment of intrathecal neostigmine containing methyl and propylparabens. Anesth Analg 1997; 85: 842–6.
25. Liu SS, Hodgson PS, Moore JM, et al. Dose-response effects of spinal neostigmine added to bupivacaine spinal anesthesia in volunteers. Anesthesiology 1999; 90: 710–7.
26. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine in humans. Anesthesiology 1995; 82: 331–43.
© 2002 International Anesthesia Research Society
27. William M, Splinter WM, Reid CW, et al. Reducing pain after inguinal hernia repair in children: caudal anesthesia versus ketorolac tromethamine. Anesthesiology 1997; 87: 542–6.