This study was approved by the Institutional Review Board of Guangzhou Women and Children’s Medical Center (IRB2013053103), and written informed patient consent was attained from the parents or legal guardians of each paediatric patient in this trial. The trial was registered prior to patient enrolment at chictr.org.cn (ChiCTR-TRC-13003492). One hundred and sixty nine ASA physical status I or II children aged from 1 to 3 years old scheduled to undergo elective hydrocele or inguinal hernia repair were recruited. Exclusion criteria included patients with neurological, psychiatric, cardiovascular, respiratory, hepatic, renal diseases or bleeding disorders; or a known allergy history of anesthetics. Using a computer-generated table and a sealed envelope with sequence of numbers, children were randomly allocated into five groups into one of the five groups: Group C (caudal ropivacaine only), Group K0.25 (caudal ropivacaine plus 0.25 mg/ml preservative free ketamine), Group K0.5 (caudal ropivacaine plus 0.5 mg/ml preservative free ketamine), Group K0.75 (caudal ropivacaine plus 0.75 mg/ml preservative free ketamine), and Group K1.0 (caudal ropivacaine plus 1.0 mg/ml preservative free ketamine). The total volume of ropivacaine with/without preservative free ketamine solution for caudal injection in all groups are 1 ml/kg.
All children underwent preoperative fasting for 6 hours and received no premedication. Sevoflurane via a face mask was used for anesthesia induction in the children. After securing intravenous access, 3 mg/kg propofol was intravenously administered to maintain sedation in a single dose or repeated doses. A caudal puncture was performed with a 22-gauge catheter by introducing in the caudal space with the patient in the left lateral decubitus position by a consultant anesthesiologist. The mixed solution of caudal injection is prepared by 0.9% saline, ropivacaine and ketamine. After felling the loss of resistance and checking for the negative presence of cerebrospinal fluid or blood, the ropivacaine with/without preservative free ketamine solution (total volume, 1 ml/kg) was administered via the catheter over 60 s. All inhalational agents were discontinued after the finish of the caudal injection. Then the patient was repositioned to supine for surgery. Continuously intravenous infused propofol (8-10 mg/kg/h) was administered to maintain sedation, and the depth of anesthesia was adjusted accordingly with the objective of achieving 80-120% baseline non-invasive mean arterial pressure. Dermatomal heights or upper limits of the caudal block were not formally assessed by pinprick before skin incision which was performed at exactly 20 minutes after the caudal injection. Baseline vital signs were collected to ensure a stable state and to discriminate slow onset of analgesia which was regarded as a confounding variable. An anesthesiologist who was unaware of the group assignments and the test concentrations of ropivacaine or ketamine collected the data and evaluated analgesic efficacy. After skin incision, the patient was observed for at least 60 seconds for hemodynamic stability and signs of purposeful movement.
The primary outcome was the MLAC of ropivacaine with/without ketamine for caudal block in children. The success of a caudal block was defined as the change in hemodynamic parameters <20% of baseline values and the absence of gross purposeful movement after skin incision. The modified Dixon’s up-and-down method was used to determine the target concentration of caudal ropivacaine for each pediatric patient, starting from 0.16% in each group, with 0.02% as a step size. According to the response of the previous patient in the same group, the target concentration of caudal ropivacaine was increased or decreased. If it failed, a 0.02% concentration of caudal ropivacaine would be increased for the next patient. If it was successful, the next child could be given caudal ropivacaine where the concentration would be decreased by 0.02%. When a response was determined to be a failure, the surgeon would stop all operations, and a rescue dose of 0.5 mg/kg ketamine would be intravenously administrated immediately to reduce the pain and could be repeated if needed during the surgery. A pair of crossover was defined as the midpoint between failed and successful caudal block in two consecutive children. And the study would be ended after collecting nine pairs of crossover in each group.
The secondary outcomes of the study were durations of analgesia. Postoperative analgesia was assessed by using the “Face, Legs, Activity, Cry, Consoling” tool (FLACC). A FLACC score of more than 4 points was considered as inadequate analgesia and was additional orally administrated 10 mg/kg ibuprofen every 6 hour as needed. The duration time of analgesia was defined from caudal block to the first postoperative rescue analgesia. An independent nurse evaluated the pain scale every hour in 8 hours after the surgery and then every 6 hour as required. Side effects like postoperative nausea and vomiting (PONV), urine retention, agitation, hypotension, bradycardia, and respiratory depression were recorded. Emergence agitation evaluation was scored by using a five-point scale. A score of ≥ 3 was defined as emergence agitation according to five-point scale (0=falling asleep peacefully; 1=quiet; 2=easy to console; 3=difficult to console with moderate agitation; 4=combative, excited, and disorientated). On the second day after surgery all children were discharged.
Statistical analyses were performed in SPSS 19.0 for Windows (SPSS Inc., USA). Data were expressed as mean (SD) or count, when appropriate. The MLAC was estimated from the up-and-down sequences with the Dixon and Massey method. The MLAC of caudal ropivacaine was analysed by calculating the midpoint concentration of all independent pairs of crossover points in each group. According to the study conducted by Paul and Fisher , nine pairs of crossover patients were needed. The variance of age, weight, duration of surgery, propofol doses and recovery time was analysed by using analysis of variance followed by a Dunnet t test or Kruskal-Wallis test. The type of surgery and adverse effects were analysed with the Chi-square test. The duration of caudal analgesia was analysed with Kaplan-Meier survival analysis and log-rank test. P <0.05 was considered statistically significant.