Using Ketamine as Adjuvant to Bupivacaine for Caudal Analgesia in Major Abdominopelvic Surgeries in Pediatrics

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1 Med. J. Cairo Univ., Vol. 84, No. 2, March: 75-80, Using Ketamine as Adjuvant to Bupivacaine for Caudal Analgesia in Major Abdominopelvic Surgeries in Pediatrics DALIA KHALED, M.Sc.; ENGY WAGDY, M.D.; MOHAMED EL-SONBATY, M.D.; RIHAM HUSSEIN, M.D. and MANAL EL-GOHARY, M.D. The Department of Anaesthesiology, Faculty of Medicine, Cairo University Abstract Background: The commonest technique for regional anaesthesia in pediatrics is considered to be the caudal anaesthesia. The main disadvantage is short duration of single shot technique. However, with the help of adjuvants used, this can be overcome. In this study we compare addition of ketamine to bupivacaine in caudal analgesia for pediatrics undergoing major abdominopelvic surgeries. Methods: 60 pediatric patients of both genders, ASA I or II, age ranging from 6 months to 3 years, undergoing elective abdominopelvic surgical procedures expected to last more than 90min., and scheduled for general anesthesia combined with caudal extradural block were recruited. Anesthesia was induced using face mask with sevoflurane 5% in oxygen. After applying standard monitoring, receiving atropine (0.02 mg/kg IV) and atracurium (0.5mg/kg IV), intubation with a suitable endotracheal tube was done. Anesthesia was maintained using isoflurane and top up doses of atracurium 0.1 mg/kg every 20 minutes with controlled mechanical ventilation. Children were randomly allocated to two groups to receive a caudal injection; CB Group (n=20): Received caudal solution of total amount of 1ml/kg containing bupivacaine 0.25% diluted in saline, while CK Group (n=20): Received caudal solution of total amount of 1ml/kg containing bupivacaine 0.25% plus ketamine 0.5mg/kg in saline. Intraoperative hemodynamic (heart rate and blood pressure) were observed with the need for intraoperative fentanyl analgesia (1µg/kg). Also postoperative hemodynamics (heart rate, blood pressure and SpO2) were observed with assessment of analgesia, CHIPP score, duration of motor block sedation, and development of any side effects until 2h postoperative. Results: Intra and postoperative hemodynamics showed lower and more stable readings in CK group compared to CB group starting at 80 minutes intraoperative and continuing till the end of two hours postoperative. Intraoperative fentanyl was consumed by 8 patients (45%) in CB group compared to none (0%) in CK group (p=0.0005). Postoperative CHIPP Score showed significantly lower readings in the CK group compared to CB group (p=0.01) throughout the postoperative period. Duration of analgesia was significantly longer in the CK group (8.95± 1.43) compared to CB group (4.725 ±3.05) Correspondence to: Dr. Dalia Khaled, The Department of Anaesthesiology, Faculty of Medicine, Cairo University (p=0.001). Duration of motor block, sedation score, postoperative side effects (urine retention, nausea and vomiting, pruritis and respiratory depression) showed no statistical significant difference between the two groups. Conclusion: Ketamine 0.5mg/kg added to bupivacaine 0.25% significantly increases potency of intraoperative analgesia and prolongs the duration of postoperative analgesia with reduction of analgesic requirements and preserved hemodynamic stability, lower postoperative pain score, lack of sedation and postoperative side effects thus allowing surgeries lasting min. to be done with single shot caudal analgesia. Key Words: Ketamine Caudal analgesia Pediatrics Bupivacaine Major abdominopelvic surgery. Introduction EPIDURAL caudal anesthesia is the commonest regional technique used for pediatric analgesia in abdominopelvic surgeries. Its popularity is due to easily identified anatomical landmarks, safety, ease of performance, availability of data on doses and pharmacokinetics of local anaesthetics and having high success and low complication rates in infants and children. It is uusually used as an adjunct to general anaesthesia. Advantages include faster and smoother emergence, reducing intraoperative use of other anaesthetic agents with a better postoperative analgesia with less side effects [1]. Nevertheless, these advantages are somewhat limited by the short duration of action of single shot technique of Local Anaesthetics (LAs). So adjunct analgesia is commonly used to prolong duration of LA analgesia and decrease the risk of side effects by reducing the dose of used LAs [2]. Ketamine is a non-competitive NMDA receptor antagonist, which inhibits central sensitization, thus potentiating the analgesic effect of epidural bupivacaine. It may have an additional analgesic effect through agonist activity at mu-opioid receptors and interaction with voltage-sensitive sodium channels [3]. 75

2 76 Using Ketamine as Adjuvant to Bupivacaine for Caudal Analgesia Aim of the work: Demonstrate the safety and effectiveness of addition of ketamine 0.5mg/kg to bupivacaine 0.25%, with plain bupivacaine 0.25%, in a singleshot caudal epidural analgesia for analgesia in major abdominopelvic surgeries in children. Patients and Methods This randomized double blinded study started December 2013 through September 2015 and has been conducted in Cairo University Specialized Pediatric Hospital with the approval of the Ethical Committee of Anesthesia Department. 60 children, aged 6 months to 3 years of age, ASA I and II, scheduled for elective major abdominopelvic surgical procedures expected to last more than 90min., and scheduled to receive general anesthesia combined with caudal extradural block were included in this study after obtaining consent from the parents of each patient. Exclusion criteria included: Parent refusal, ASA III or greater, history of allergy or hypersensitivity to local anesthetics or ketamine, and contraindications to caudal anesthesia. We used an online randomization program to generate random number list ( randomizer.org/). Patient randomization numbers were concealed in opaque envelops which were opened by the study investigator in charge of preparation of the study drug. Patients were randomly allocated into one of the study groups. Patients did not receive preoperative sedation to allow assessment of sedative effect of the drugs to be tested. Arriving to the OR, standard monitors were applied. Anesthesia was induced via face mask with sevoflurane 5% in 100% oxygen. After loss of consciousness an IV cannula was placed peripherally and atropine (0.02mg/kg IV) was given. After achieving an adequate depth of anesthesia (judged by centralization of the eye ball) atracurium (0.5mg/kg IV) was given, to facilitate intubation using a suitable sized endotracheal tube. Anesthesia was maintained with isoflurane and top up doses of atracurium 0.1mg/kg every 20 minutes and controlled mechanical ventilation. Caudal anesthesia was performed with the patient in the lateral position, using a 22-gauge short beveled needle (4cm in length), with negative aspiration test done to exclude intravascular or intrathecal placement then injection of study solution was done slowly and during injection a whoosh test was done for identifying correct needle placement in the caudal canal. The child was immediately turned supine after injection of the drug. CB Group (n=20): Received caudal solution of 1 ml/kg containing bupivacaine 0.25% in Saline. CK Group (n=20): Received caudal solution of 1 ml/kg containing bupivacaine 0.25% plus ketamine 0.5mg/kg in saline. Increasing HR or MAP within 15 minutes of skin incision indicated failure of caudal anesthesia. Increased readings >15%, indicate inadequate analgesia and rescue opioid (fentanyl 1mg/kg) was given. Fluid therapy during surgery included D5 in 0.45% saline used utilizing formula of 4-2-1ml/Kg body weight to replace the deficit, Ringer's lactate was used as maintenance fluid and as replenish for third space losses as IV infusion at the rate of 10 ml/kg/h, and blood in the form of packed RBCs if needed. Intraoperative decreased MAP or HR >15% of the baseline reading, was defined as hypotension or bradycardia, respectively, and was treated by fluid bolus, a vasoconstrictor (ephedrine) or atropine as needed. At the end of of surgery, patients were recovered from anesthesia and transferred to PACU with monitoring of HR, noninvasive BP, SpO 2 and pain scoring. If the CHIPP score was >4 or if the patient showed obvious signs of pain, supplementary analgesia in the form of 15mg/kg rectal paracetamol suppository was given. Parameters recorded: *Intraopertive: 1- Number of patients receiving intraoperative Fentanyl analgesia. 2- Hemodynamics: Heart rate and mean arterial blood pressure recorded starting 5min. before the induction of anesthesia (baseline value), after induction but 5min. before caudal anesthesia, and then every 20min. after caudal anesthesia during operation and every 30 minutes after the end of operation and recovery till the end of 2h after the end of operation and extubation. *Postoperative: 1- CHIPP score: Analgesic assessments made every 30min. after extubation of the patient for two hours, in PACU using the children and infants postoperative pain scale to assess five behavioral objective variables (crying, facial expression, position of trunk, position of legs, motor restlessness), where each variable scores 0-2 (0= none, 1=moderate, 2=severe) to give a cumulative score of 0-10 to qualify analgesia. 1- Quiet

3 Dalia Khaled, et al. 77 child (no need for intervention). 2- A child that could be comforted (requiring physical contact with parents). 3- Restless child (crying). 4- Child in aggressive mode (requiring physical control to prevent harming themselves) [4]. 2- Sedation score: Assessment every 30min. till 2 hours after recovery with an objective score based on eye-opening: - Eyes open spontaneously=0 (not sedated), - Eyes open in response to verbal stimulation=1 (mildly sedated), - Eyes open in response to physical stimulation=2) (heavily sedated) [5]. 3- Duration of analgesia: Time from caudal block to first postoperative analgesic administration (paracetamol). 4- Side effects including: Urine retention (Time of first void), nausea and vomiting (PONV), pruritus and respiratory depression (SpO 2 <95% on room air). Statistical methods: All data were statistically described in terms of mean ± Standard Deviation (SD) median and percentages when appropriate. For repeated measurements among the same group repeated measure ANOVA was used. p-value less than 0.05 was considered statistically significant. For comparing categorical data, Chi square ( χ 2 ) test was performed. All statistical calculations were done using SPSS) version Results Regarding demographic data, duration and type of surgery, there was no statistically significant difference between the study groups. Average duration of surgery was 2-3 hours in both groups (Table 1). I- Number of patients receiving intraoperative Fentanyl analgesia: There was a statistically significant difference between the numbers of patients who received intraoperative fentanyl in CB group (used in 8 patients, 45%) compared to CK group (none). ( p- value=0.0005) (Table 2). II- Hemodynamics: Heart Rate (HR): Intraoperative HR, showed no statistically significant difference between the study groups until the 80 minutes reading in CK group was lower compared to CB group, and this difference was statistically significant ( p-value =0.04). The postoperative readings showed the same pattern with CK group being significantly lower than CB group (Table 3). Mean Arterial Pressure (MAP): Intraoperative readings revealed statistically significant difference with lower MAP in the CK group at 80 minutes compared to CB group (p-value=0.012). This difference continues till the end of operation and throughout postoperative period till two hours after end of operation (Table 4). III- Postoperative CHIPP score [4] : There was a statistically significant difference where the CB group showed significantly lower pain score readings than CB group starting at 30min. postoperative till the end of postoperative two hours. (p-value=0.0001) (Table 5). IV- Postoperative sedation score [5] : There was no significant postoperative sedation or statistically significant difference comparing both groups (p-value>0.05) (Table 6). V- Duration of analgesia: Assessed by the time to first postoperative rescue analgesia, which was more prolonged in patients of CK group compared to CB group and this prolongation was statistically significant ( p- value=0.001) (Table 7). VI- Postoperative side effects: Urine retention: There was no statistically significant difference comparing the time to first void among study groups (p-value >0.05), and the time to first void showed no urine retention among the groups (Table 7). Nausea and vomiting: There was no statistical difference between the groups regarding side effects like nausea and vomiting (p-value >0.05) (Table 7). Pruritus: There were no reported cases among the groups (Table 7). Respiratory depression: There were no reported cases among the groups (Table 7). Table (1): Demographic data, duration and type of surgery. Age (years) 2.145± ±0.528 Sex: Male 8 (45%) 13 (55%) Female 12 (54%) 7 (44%) Weight (kg) 12.95± ±2.04 Duration of surgery (min) 124.9± ±5.2 Type of surgery: Urological 7 (35%) 8 (40%) Orthopaedic pelvic 6 (30%) 5 (25%) Intestinal 7 (35%) 7 (35%) Data are presented as mean ± SD and number of patients (%).

4 78 Using Ketamine as Adjuvant to Bupivacaine for Caudal Analgesia Table (2): Intraoperative fentanyl analgesia. Intra-operative fentanyl 8 (45%) 0 (0%)* CB: Control (bupivacaine) group. Data are presented as number of patients (%). Table (3): Heart rate measurements throughout the study period. HR Preoperative (baseline). 5min. (before block) ± ± ± ± 10.1 After block: 20min ± ± min. 138.± ± min ± ± min. 100min ± ± ± 13.8* 125.7± 12.8* 120min ± ± 12.6* Postoperative 30min ± ± ± 13.8* 125.7± 12.6* 126.2± 12.2* 124.6± 12.2* 60min. 90min ± ± min ± ± 11.1* CB: Control (bupivacaine) group. Data presented as Mean ± SD. *: Significant p-value <0.05 vs. the corresponding measurement in CB group (one way anova). Table (4): MAP measurements throughout the study period. MAP Preoperative (baseline) ± ±6.82 5min. (before block) ± ±6.73 After block: 20min ± ± min. 60min. 6.75± ± ± ± min. 100min. 59.4± ± ±5.06* 5.75±4.97* 120min ± ±4.16* Postoperative 61.8±7.5 56±4.16* 30min. 60min ± ± ±5.82* 54.05±4.21* 90min ± ±6.18* 120min ± ±6.6* Data presented as Mean ± SD. *: Significant p-value <0.05 vs. the corresponding measurement in CB group (one way anova). Table (5): Postoperative CHIPP score [4]. 30min. 2 (1-3) 2 (0-2)* 60min. 3 (2-3) 2 (0-3)* 90min. 3 (2-3) 2 (0-3)* 120min. 3 (3-4) 3 (2-3)* Data are presented as median (range). Table (6): Postoperative sedation score [5]. Postoperative sedation 30min. 2 (2-3) 3 (2-3) 60min. 1 (1-2) 1 (1-2) 90min. 1 (1-2) 1 (1-2) 120min. 1 (1-2) 1 (1-2) Data presented as median (range). *: Significant p-value <0.05 vs. CB group (one-way anova). Table (7): Duration of postoperative analgesia. Onset of postoperative pain (hour) 4.725± ± 1.43* CB: Control (bupivacaine) group. Data presented as mean ± SD. *: Significant p-value <0.05 vs. CB group (one-way anova). Table (8): Postoperative side effects. First void (hour) 1.75±0.76 2±0.66 Nausea & vomiting 3 (15%) 2 (10%) Pruritus 0 (0%) 0 (0%) Respiratory depression 0 (0%) 0 (0%) Data presented as mean ± SD and number of patients (%). Discussion Caudal epidural block is the most commonly used regional analgesic techniques in pediatric surgeries. It is safe and effective in management of intraoperative pain and hemodynamic instability as it attenuates somatic, autonomic and endocrine responses to pain. The main disadvantage with the single shot technique is short duration of action. Therefore it's a common practice to use pharmacological adjuvants to overcome this disadvantage [6]. Ketamine is a noncompetitive N-Methyl-D- Aspartate glutamate (NMDA) receptor antagonist. The commercial preparation of ketamine is a racemic mixture of two enantiomers, S(+) and R( ), which exhibit pharmacologic and clinical differences. The S(+) enantiomer is four times more potent than R() enantiomer and has twice the analgesic potency. The inhibitory effect of S(+) ketamine on the NMDA receptor was reported as three times greater than that of the R( ) ketamine. The S(+) isomer is cleared more rapidly, resulting in a shorter duration of action and more rapid recovery. The compound has a faster offset, allow-

5 Dalia Khaled, et al. 79 ing more easily titrated use when using infusions. Besides its role as an NMDA receptor antagonist, ketamine induces an analgesic effect by nitric oxide synthase inhibition [7]. Ketamine is a popular drug, used for different purposes. It can be administered by almost any route and combined with various sedative and analgesic agents. The dose used to enhance the effect of LAs when performing caudal blocks in children ( mg/kg) is close to that used IV (1-2mg/kg) or even IM (4-5mg/kg) to induce anaesthesia [8]. The drug has a well-established role in pediatric anesthesia for induction and maintenance of GA and may be used specifically in certain procedures as children with neuromuscular disorders potentially at risk of developing malignant hyperthermia, and also in children with cyanotic heart disease, as it increases systemic vascular resistance and cardiac output and does not worsen left-to-right shunting. It is also valuable for analgesia in the first 12 hours after the operations, and in combination with other short-acting anesthetic agents, with lower target blood concentrations for anesthesia [9]. Ketamine is being used for procedural sedation because of its acceptably short duration of action, safety profile, administration through almost any route, and sedative/analgesic effects. It is a popular drug for use in dentistry, emergency department, dermatology, plastic procedures, and interventional radiology in children. Ketamine produces a state of dissociative sedation. It also has an analgesic action at many sites both centrally and peripherally [10]. The use of ketamine in regional anesthesia in children is increasing as it provides satisfactory operating conditions and excellent perioperative analgesia. Ketamine provides satisfactory perioperative analgesia as a sole agent in pediatric caudal block [11]. In our study there were lower hemodynamic readings in CK group, starting at 80 minutes intraoperative and continuing till the end of 2 hours postoperative for HR ( ± 13.8) compared to CB group (136± 16.7) and for MAP (53.15 ±5.06) compared to CB group (61.85 ±8.62), with the need of intraoperative fentanyl analgesia (1µg/kg) in 8 patients (45%) in CB group compared to none in CK group. These result matched the results obtained by Elderwy et al., [12], who demonstrated that addition of caudal ketamine (0.5mg/kg) to bupiv- acaine 0.25% (1ml/kg), compared to magnesium sulfate (50mg) added to caudal bupivacaine in children (3-10 years) undergoing inguinoscrotal surgeries. The study showed significantly lower intraoperative HR and MAP readings and postoperative HR readings in the ketamine group compared to the magnesium sulfate group. Our study showed a significant decrease in the pain score in CK group compared to CB group starting at 30min. postoperative till the end of 2 hours. Chaudhary S. et al., (2015), [13] used the modified visual analog scale to assess pain after till 24 hours postoperative. The score was significantly lower with ketamine (0.5mg/kg) when compared to bupivacaine alone (0.25%, 1mg/ml), used for inguinal procedures in children (2-10 years). No statistically significant difference in sedation in any of the study groups starting 15 minutes postoperative and for 2 hours was demonstrated in our study, as Elderwy et al., [12]. However, unlike our results, in the study by Chaudhary S. et al., (2015), [13] showed more sedation with ketamine group compared to bupivacaine only group. This may be explained by the fact that oral midazolam 0.4mg/kg was given to the patients, 30min. prior to induction of anesthesia using sevoflurane or propofol in older children, however, sedation scores after initial 30min. were not significantly different. Our study showed a clinically significant prolongation in the time to the first postoperative rescue analgesia in CK group (8.95 ± 1.43) compared to CB group (4.725 ±3.05). In Chaudhary et al., [13]and Elderwy et al., [12] studies, time to postoperative rescue analgesia was significantly prolonged, with a significant decrease in the amount of supplemental rescue analgesia requirements (paracetamol 15mg/kg rectal) used within 12 hours postoperative in the ketamine group. Regarding postoperative side effects (urine retention, respiratory depression, pruritis, nausea and vomiting) there was no statistically significant difference between the studied groups. The neurotoxic effects of ketamine after intrathecal administration were observed in animal studies [14]and after continuous intrathecal administration for the management of neuropathic cancer pain [15]. But human studies showed that the use of caudal ketamine at a dose of not more than 0.5 mg/kg significantly diminishes the risk of associated neurotoxic effects [12,13].

6 80 Using Ketamine as Adjuvant to Bupivacaine for Caudal Analgesia Conclusion: The present study, concluded that the use of ketamine as adjuvant to local anesthetic bupivacaine, during single dose injection in caudal analgesia provided a better intraoperative analgesia and a more satisfying levels postoperative analgesia than bupivacaine alone, following major lower abdominopelvic surgery in pediatrics. Furthermore, the duration of sedation and the postoperative side effects, including urine retention, nausea and vomiting, pruritis and respiratory depression, recorded in the PACU showed no significant difference among the studied groups. References 1- VAN SCHOOR A.: Pediatric regional anaesthetic procedures: Clinical anatomy competence, pitfalls and complications [Master dissertation]. Pretoria, University of Pretoria, Nysora.com. 'NYSORA-The New York School of Regional Anesthesia-Toxicity Of Local Anesthetics'. N.p., BECKER D.E. and REED K.L.: Local anesthetics: Review of pharmacological considerations. Anaesthesia Program, 59 (2): ; quiz 102-3, WU C.L., BERENHOLTZ S.M., PRONOVOST P.J., et al.: Systematic review and analysis of post-discharge symptoms after outpatient surgery. Anesthesiology, 96: , KLEINMAN W. and MIKHAIL M.S.: Spinal, epidural and caudal blocks. In Morgan G.A., Mikhail M.S., Murray M.J.: Clinical Anesthesiology, 4 th ed. Lange Medical Books/McGraw Hill, pp , BAJWA, SUKHMINDER JIT SINGH, et al.: 'Comparative Evaluation Of Dexmedetomidine And Fentanyl For Epidural Analgesia In Lower Limb Orthopedic Surgeries'. Saudi Journal of Anaesthesia, 5.4: 365, BREDLAU A.L., THAKUR R., KORONES D.N. and DWORKIN R.H.: "Ketamine for pain in adults and children with cancer: A systematic review and synthesis of the literature". Pain Medicine, 14 (10): , SIH K., CAMPBELL S.G., TALLON J.M., MAGEE K. and ZED P.J.: Ketamine in adult emergency medicine: Controversies and recent advances. Ann. Pharmacother, 45: , DAHMANI S., MICHELET D., ABBACK P.S., et al.: Ketamine for perioperative pain management in children: A meta-analysis of published studies. Paediatr. Anaesth., 21: , SCHNABEL A., POEPPING D.M., KRANKE P., ZAHN P.K. and POGATZKI-ZAHN E.M.: Efficacy and adverse effects of ketamine as an additive for paediatric caudal anaesthesia: A quantitative systematic review of randomized controlled trials. Br. J. Anaesth., 107: , BHUTTA A.T.: Ketamine: A controversial drug for neonates. Semin. Perinatol., 31: 303-8, ELDERWY A., FARRAG W.H., IBRAHIM A., MOSTAFA M. and KURKAR A.: 'Ketamine Versus Magnesium Sulfate With Caudal Bupivacaine Block In Pediatric Inguinoscrotal Surgery: A Prospective Randomized Observer-Blinded Study'. Urol. Ann., 7 (3): 325-9, CHAUDHARY, SUJATA, et al.: 'Efficacy Of Caudal Fentanyl And Ketamine On Post-Operative Pain And Neuroendocrine Stress Response In Children Undergoing Infraumbilical And Perineal Surgery: A Pilot Study'. J. Anaesthesiol. Clin. Pharmacol., 31.1: 104, VRANKEN J.H., TROOST D., HAAN P., PENNINGS F.A., VEGT M.H., DIJKGRAAF M.G. and HOLLMANN M.W.: Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)- ketamine. Anesthesiology, 105 (4): 813-8, VRANKEN J.H., TROOST D., WEGENER J.T., KRUIS M.R., VEGT M.H.: Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain. Pain, 117 (1-2): 231-5, 2005.