|Year : 2016 | Volume
| Issue : 3 | Page : 426-431
Preservative-free racemic ketamine with bupivacaine: a desirable option for extended caudal analgesia in pediatric surgery
Deepa Chandramohan MD, DNB, FCCM , Shirley A DíSouza
Department of Anesthesiology and Critical Care, Goa Medical College, Goa, India
|Date of Submission||19-Aug-2015|
|Date of Acceptance||03-Apr-2016|
|Date of Web Publication||31-Aug-2016|
F-4, Block-3, Rich Builders Hill View, Bambolim, Goa 403 202
Source of Support: None, Conflict of Interest: None
Caudal epidural block is a commonly performed procedure in pediatric anesthesia worldwide. Ketamine is used as an adjuvant in single-shot caudal blocks to prolong postoperative analgesia.
Aims of the study
This randomized double-blind study was carried out to evaluate the effect of the addition of preservative-free racemic ketamine 0.5 mg/kg to 0.25% bupivacaine (1 ml/kg) in caudal block on the duration of postoperative analgesia in pediatric patients and to observe adverse effects, if any.
Materials and methods
Sixty children, aged 2–9 years, undergoing infraumbilical surgical procedures were assigned randomly to one of two groups, B or BK, to receive 1 ml/kg of 0.25% bupivacaine or a mixture of 0.5 mg/kg of preservative-free racemic ketamine with 1 ml/kg of 0.25% bupivacaine, respectively, for single-shot caudal anesthesia. The postoperative pain score was assessed. Sedation, motor weakness, and other adverse effects were also observed.
Observations and results
The mean duration of analgesia was significantly longer (P < 0.01) in group BK (12.933 h) than in group B (3.467 h). The incidences of adverse effects such as urinary retention, vomiting, and motor weakness were comparable in the two groups (P > 0.05).
Preservative-free racemic ketamine at a dose of 0.5 mg/kg may be used as a safe and reliable adjunct to caudal bupivacaine for prolongation of postoperative analgesia in children. As racemic ketamine is less expensive and more easily available than S(+)-ketamine, further studies comparing their cost-effectiveness may help to establish the racemic preparation as an appropriate adjuvant for single-shot caudal analgesia, especially in nations where cost constraints exist.
Keywords: bupivacaine, caudal analgesia, ketamine, preservative-free, racemic
|How to cite this article:|
Chandramohan D, DíSouza SA. Preservative-free racemic ketamine with bupivacaine: a desirable option for extended caudal analgesia in pediatric surgery. Ain-Shams J Anaesthesiol 2016;9:426-31
|How to cite this URL:|
Chandramohan D, DíSouza SA. Preservative-free racemic ketamine with bupivacaine: a desirable option for extended caudal analgesia in pediatric surgery. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Apr 14];9:426-31. Available from: http://www.asja.eg.net/text.asp?2016/9/3/426/189573
| Introduction|| |
Caudal epidural anesthesia is one of the most regularly performed regional procedures in pediatric anesthesia worldwide. In addition to being simple, safe , and having a high success rate ,, it supplements general anesthesia during surgery and also provides analgesia in the postoperative period for pediatric patients undergoing various surgical procedures. Single-shot caudal block has the disadvantage of rendering only relatively short duration of postoperative analgesia even with the use of long-acting local anesthetic (LA) agents, such as bupivacaine and ropivacaine . The use of a caudal epidural catheter for the purpose of prolonging postoperative analgesia is undesirable as it predisposes to infection because of the likelihood of fecal contamination.
The use of various opioid additives , such as tramadol, morphine, fentanyl, and sufentanil in single-shot caudal block for prolongation of analgesia did not gain much popularity, especially in the outpatient settings, because of their adverse effects such as delayed respiratory depression, excessive sedation, urinary retention, nausea, and vomiting. Currently, various nonopioid adjuvants ,, such as clonidine, dexmedetomidine, and midazolam are being used to provide long-lasting analgesia in the postoperative period.
Ketamine has been found to prolong postoperative caudal analgesia ,,,,,, through its ‘uncompetitive’ antagonistic activity at the N-methyl D-aspartate (NMDA)-type glutamate receptors . Although the safety of ketamine for use in caudal block is still being questioned because of the potential neurotoxicity , no major or permanent neurological sequelae have been reported to date with its use in single-shot caudal blocks in human studies .
This randomized double-blind study was carried out to evaluate the effect of the addition of preservative-free racemic ketamine 0.5 mg/kg to 1 ml/kg of 0.25% bupivacaine in caudal block on the duration of postoperative analgesia in pediatric patients undergoing infraumbilical surgeries and to observe adverse effects, if any.
| Materials and methods|| |
The study was carried out over a period of 24 months (1 January 2007 to 31 December 2008) at Goa Medical College, Goa, India. Sixty children, aged 2–9 years, weighing less than 20 kg, American Society of Anesthesiologists physical status I, scheduled to undergo infraumbilical surgical procedures (inguinal herniotomy, circumcision, and hypospadias repair) in our tertiary care teaching hospital were selected for the study. Children with a history of allergic reactions to bupivacaine or ketamine or those with any contraindication for central neuraxial blockade were excluded from the study. The institutional ethical committee approved the study and a written informed parental consent was obtained for each patient. The sample size was determined on the basis of a pilot study that we had carried out, with the help of G*Power 3.1.6 software (Department of Psychology, University of Dusseldorf, Germany). Considering an effect size of 2.51, confidence level of 95%, and power of 0.9, with an allocation ratio of 1, the total sample size was calculated to be 10. We included 60 children in our study, 30 in each of the two study groups. Each patient was allocated randomly using a computer-generated list to one of two groups: B or BK. Group B (n = 30) was scheduled to receive 1 ml/kg of 0.25% caudal bupivacaine, whereas group BK (n = 30) was scheduled to receive a mixture of 1 ml/kg of 0.25% caudal bupivacaine with 0.5 mg/kg of preservative-free racemic ketamine.
Midazolam 0.5 mg/kg was administered orally as premedication 20–30 min before induction of general anesthesia. General anesthesia was induced with intravenous thiopentone (2.5%) 5 mg/kg through a 22- or a 24-G intravenous cannula. Anesthesia was maintained using nitrous oxide (66%), oxygen (33%), and halothane (0.5–1%) delivered through a mask and Jackson Ree's breathing circuit with spontaneous ventilation. Caudal block was administered in the left lateral position using a 23-G short-beveled needle under aseptic conditions. After confirming correct placement of the needle by the ‘swoosh’ test  and negative aspiration of blood and cerebrospinal fluid, the respective drug solution was injected. A sterile dressing was placed over the site of the injection and the child was placed in supine position. Surgery commenced 10–15 min after the caudal injection.
Heart rate (HR), mean arterial blood pressure (MAP), respiratory rate, and oxygen saturation (SpO2) were recorded before induction of anesthesia and then every 5 min after the administration of caudal anesthesia for the first 30 min and every 10 min thereafter. During surgery, adequate analgesia was indicated by hemodynamic stability, as noted by the absence of an increase in MAP or HR by greater than 15% of preincision baseline values. If the block provided adequate analgesia, the end-tidal halothane concentration was decreased gradually to 0.5%. An increase in HR or MAP within 15 min of skin incision indicated failure of caudal anesthesia. In case of inadequate analgesia, the child was administered intravenous fentanyl 2 μg/kg. An intraoperative decrease of MAP or HR by more than 30% was defined as hypotension or bradycardia, respectively, and was treated by intravenous fluid bolus, intravenous ephedrine, or intravenous atropine, as necessary. During surgery, intravenous Ringer's lactate solution was infused according to the Holliday and Segar 4-2-1 rule . The time from induction of general anesthesia to the end of surgery when the inhalational anesthetic agents were discontinued was noted. Each patient was observed for 2 h in the operation theater recovery room before being transferred to the ward. On arrival in the recovery room, pain, sedation, and motor block were evaluated. Respiratory rate, HR, and SpO2 were monitored continuously in the recovery room.
Postoperative pain was assessed using a ‘five-point verbal pain score’  [1 = asleep, 2 = awake; but no pain, 3 = mild pain (pain on touching the area or on movement), 4 = moderate pain (constantly cries or complains of pain), and 5 = severe pain (uncontrollable or excessive crying)]. The visual analogue score (10-cm horizontal scale) could not be used in our study because it was not well understood by all the children in the study. The duration of absolute analgesia was defined as the time from caudal injection up to a pain score of at least 2. Rescue analgesic was administered for a pain score of 4 or more in the form of oral paracetamol (15 mg/kg). Sedation was assessed using the ‘three-point objective sedation score’  on the basis of eye opening (1 = awake; 2 = awake, but drowsy; 3 = unarousable). A score of 2 or 3 was considered as sedation. Motor block was assessed on awakening using the Bromage scale  (grade I – free movement of legs and feet, grade II – just able to flex knees with free movement of feet, grade III – unable to flex knees, but with free movement of feet, grade IV – unable to move legs or feet). Younger children who could not move their legs on command were stimulated on the legs and feet. All those who had motor block of grade II or more, on being discharged from the operation theater recovery room, were reassessed for motor block later at 6 h from the time of caudal injection. Assessments were repeated in the recovery room just before being shifted to the ward and then at 4, 6, 8, 10, 12, 14, and 24 h after the caudal injection in all patients. The incidences of adverse effects such as nausea, vomiting, sleep disturbance, abnormal behavior, urinary retention, and nystagmus up to 24 h were evaluated by a yes/no survey. Respiratory depression was defined as a respiratory rate less than 10 breaths/min. All evaluations were performed along with assessments of pain and sedation.
The data collected were tabulated according to various epidemiological and statistical parameters. Parametric data (e.g. duration of postoperative analgesia) were presented as mean ± SD, whereas nonparametric data (e.g. number of supplemental analgesic doses, incidence of adverse effects) were presented as numbers and percentages. Statistical analysis was carried out using an unpaired t-test for comparison of parametric data and Fisher's exact test for comparison of nonparametric data. A P value of 0.05 or less was considered to be statistically significant.
Observations and results
The two groups were well matched in their demographic characteristics and in the duration of surgery [Table 1]. The two groups were well matched for the number and type of surgical procedures, suggesting postoperative pain of similar intensity [Table 2]. During surgery, all patients were observed to have adequate analgesia, which was indicated by hemodynamic stability. There were no cases of ‘failed’ caudal block.
The mean duration of analgesia [Figure 1] in group BK was 12.933 ± 2.016 h and that in group B was 3.467 ± 0.899 h (P < 0.01). The mean number of doses of oral paracetamol required in the first 24 h was significantly (P < 0.01) lower in group BK (2.2) than that in group B (3.6). In group BK, majority (70%) of the patients required only two doses of analgesic supplements in the first 24 h, whereas all those in group B needed three or more doses of supplemental analgesics (P < 0.001) [Figure 2]. Among the total of 37 patients who required three or more doses of analgesics during the first 24 h, majority (81%) belonged to group B [Figure 3]. None of the patients in group BK required more than four doses of analgesic supplements in the first 24 h.
|Figure 2 Proportion (%) of patients in the two study groups requiring supplemental analgesics during the first 24 h (P < 0.001).|
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|Figure 3 Majority of patients who received three or more doses of supplementary analgesics during the first 24 h belonged to group B.|
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None of the patients in either group had a postoperative sedation score of 3 in the first 2 h postoperatively [Table 3]. Although 17% patients in group BK had a sedation score of 2 compared with 10% in group B, the difference was found to be statistically nonsignificant (P > 0.05). Postoperative urinary retention occurred in three (10%) and five (16.7%) patients in group BK and group B, respectively. Six patients (20%) in group BK and nine patients (30%) in group B experienced postoperative vomiting. Nystagmus occurred in only one patient (3.3%) in group BK, whereas none in group B had nystagmus. Motor weakness lasting beyond 6 h occurred in two (6.7%) and four (10%) patients in group BK and group B, respectively. Although the incidences of adverse effects [Table 4] such as urinary retention, vomiting, and motor weakness were higher in group B compared with group BK, the difference was not statistically significant (P > 0.05). The incidence of nystagmus was also found to be statistically nonsignificant (P > 0.05). None of the patients in either group had hypotension, bradycardia, behavioral abnormalities, or toxic reactions to bupivacaine or ketamine during or after administration of the caudal blocks.
|Table 3 Sedation score in the first 2 h after administration of caudal block|
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| Discussion|| |
Ketamine is known for its analgesic effects because of its antagonistic activity at the NMDA type of glutamate receptors. We used racemic ketamine in our study as it is less expensive and more commonly available than S(+)-ketamine. It was observed that caudal administration of 0.5 mg/kg of racemic ketamine with bupivacaine provided longer postoperative analgesia than bupivacaine alone without inducing significant adverse effects. Our observations were similar to those reported in previous studies ,,,,, which noted significant prolongation in the duration of caudal analgesia in pediatric patients when ketamine was used as a caudal adjuvant to bupivacaine. The bupivacaine groups in these studies required more doses of analgesic supplements than the bupivacaine–ketamine groups during the first 24 h of the postoperative period, which was similar to what we observed in our study. None of these authors noted any significant difference in the incidence of adverse effects between their study groups.
The primary mechanism of ketamine analgesia is the ‘uncompetitive antagonism’ of the NMDA type of glutamate receptors , which play an important role in processing of nociceptive stimuli. They are located throughout the central nervous system as well as in the substantia gelatinosa of the spinal cord. The antinociceptive properties of ketamine have also been associated with its interaction with μ-opioid receptors . In addition to having structural similarities to bupivacaine, ketamine interacts with sodium channels in a manner similar to LAs and even shares a binding site with the commonly used LAs . Other mechanisms include actions on voltage-sensitive calcium channels, monoaminergic channels, serotoninergic (5-HT2) receptors, nicotinic and muscarinic receptors, and enhancement of endogenous levels of dopamine and serotonin .
Racemic ketamine has been recognized to prolong caudal analgesia when coadministered with LAs ,,,,. The optimal dose of racemic ketamine for the addition to 0.25% bupivacaine intended for prolongation of single-shot caudal analgesia without significant adverse effects is 0.5 mg/kg ,. The S(+) enantiomer of ketamine, that is, S(+)-ketamine, at a dose 0.5 mg/kg, added to LAs for caudal blockade has also been shown to prolong the duration of postoperative analgesia ,. The anesthetic potency of S(+)-ketamine is twice that of the racemic mixture owing to its higher stereoselective affinity for the NMDA receptors . Even though this increase in the affinity of S(+)-ketamine has contributed toward a decrease in its intravenous dose required to induce general anesthesia and consequently, shorter recovery time and lower incidence of psychological side effects, there has been no appropriate recommendation on its dose as a caudal adjuvant for prolongation of postoperative analgesia. Racemic ketamine is less expensive and more easily available than S(+)-ketamine. In addition, the incidence of psychological side-effects is the same with both racemic and S(+)-ketamine at equal plasma concentrations . No study has yet compared either the analgesic efficacy of these two preparations of ketamine in caudal blockade or their plasma concentrations and adverse effect profile following caudal administration. The dose of S(+)-ketamine equivalent to the recommended dose of racemic ketamine (0.5 mg/kg) as an adjuvant to LAs for the purpose of prolongation of caudal analgesia is yet to be determined and their cost-effectiveness needs to be compared. Further studies in this respect may help in selecting racemic ketamine as a suitable additive for pediatric caudal analgesia, especially in nations where cost is a limiting factor.
Even though no major or permanent neurological sequelae have been notified with the use of preservative-free racemic for single-shot caudal block in human studies, the safety of ketamine for use in caudal block is still disputed . The only reported case of neurotoxicity in humans  was in 1999, where the authors concluded that the post-mortem findings of focal lymphocytic vasculitis in the spinal cord close to the catheter injection site may be related to the preservative benzethonium chloride or the toxicity of the clonidine–morphine–bupivacaine mixture itself. Despite various published reports of safe use of preservative-free caudal ketamine, this substance has not been incorporated into clinical practice widely because of the ongoing concerns of potential neurotoxicity of the preservative agents chlorobutanol and benzethonium chloride present in commercially available preparations. Before the availability of animal data reporting toxicity, racemic ketamine had been used extensively to prolong single-shot caudal analgesia in pediatric patients, with no apparent clinical toxicity . As it is the preservative and not ketamine per se, when administered intrathecally, that has been shown to cause neurotoxicity , only preservative-free preparations of ketamine in subanesthetic doses and within the setting of clinical trials are recommended at present, for use in neuraxial blockade.
In our study, we observed a significant prolongation of postoperative caudal analgesia and reduced requirement of supplementary analgesics with the use of preservative-free racemic ketamine along with bupivacaine in caudal block, without any considerable adverse effects. Racemic ketamine appears to be a satisfactory and desirable adjuvant for prolonging single-shot caudal analgesia in pediatric patients.
| Conclusion|| |
Preservative-free racemic ketamine at a dose of 0.5 mg/kg may be used as a safe and reliable adjunct to caudal bupivacaine, eliminating the use of an epidural catheter for prolongation of postoperative analgesia in children. As racemic ketamine is less expensive and more easily available than S(+)-ketamine, further studies comparing their cost-effectiveness may help to establish the use of the racemic preparation as an appropriate adjuvant for single-shot caudal analgesia, especially in nations where cost constraints exist.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]