Study design and participants
This randomized controlled clinical trial was approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (Beijing, China, KY2015–009-01). Written informed consent was obtained from all patients’ parents. This study was conducted at a single tertiary medical center (Beijing Tiantan Hospital) and indexed in the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx, ChiCTR-IOC-15007676).
The inclusion criteria were as follows: Patients aged 1–12 years, with American Society of Anesthesiologists physical status grades I–III undergoing open craniotomy procedures. Eligible subjects included patients undergoing surgery for brain tumors, craniofacial reconstruction and vascular malformations. Exclusion criteria included: Mental disorders; unsuitability for extubation; and development of hematomas or severe brain edema 3 days after surgery, requiring a subsequent operation. Additionally, we excluded patients with a history of allergy to opioids or other anesthetics, and those with a history of substance abuse. Patients were enrolled in this study only after obtaining written informed consent from their parents.
Standard monitoring was implemented in the operating room. All children were monitored for non-invasive blood pressure (BP), heart rate (HR) and pulse oximetry (SpO2); as well as invasive arterial pressure (ARP), end-tidal carbon dioxide partial pressure (PETCO2), and minimum alveolar concentration (MAC). Midazolam 0.025–0.075 mg/kg and methylprednisolone sodium succinate 1–2 mg/kg were given before surgery. If necessary, patients were given oral midazolam 0.5 mg/kg to reduce anxiety before venous access.
Anesthesia was induced with the following approximate doses: Propofol (2 mg/kg), cisatracurium (0.2 mg/kg), and sufentanyl (0.3 μg/kg) or fentanyl (3 μg/kg). In patients aged < 5 years or those unable to cooperate with the anesthesiologist, tracheal intubation was performed under induction with 6–8% sevoflurane inhalation before peripheral venous access. Prior to surgical incision, local infiltration with 0.5% ropivacaine was performed at the surgical site, and surgical pin sites was placed. Anesthesia was maintained with 0.5 MAC sevoflurane at an inhalational concentration of 2–3%, and an intravenous infusion with remifentanil 0.1–0.2 μg/kg/min and propofol 3–5 mg/kg/h. Mean arterial blood pressure and heart rate were maintained within 20% of baseline measures. 30 min before the end of the operation, additional sufentanyl 5 μg or fentanyl 0.5–1 μg/kg was administered, while inhalation of sevoflurane and the infusion of remifentanil and propofol was stopped at the end of the operation. The parameters for mechanical ventilation were set to volume control with a tidal volume of 8–10 ml/kg and a respiratory rate of 14–20 times/min. Controlled mechanical ventilation maintained PETCO2 of 30–35 mmHg using a 50% oxygen-air gas mixture. Additional rocuronium was administered, if needed, to maintain a train-of-four count of 2–3 intraoperatively. Whether patients received a central and arterial cannula after anesthesia induction was according to the needs of the operation.
Postoperative pain treatment protocol
After surgery, patients aged 1–6 years received a pump for nurse-controlled intravenous analgesia (NCIA), while those aged 7–12 received one for patient-controlled intravenous analgesia (PCIA). Based on our previous cohort study of pediatric postoperative analgesia, we found that only 12% in 1–6 years old and 58% in 7–12 years old patients used PCIA or NCIA after craniotomy . Same results were obtained in another cohort study performed by Maxwell LG7. That means that single intravenous administration after operation is a common method of postoperative analgesia in pediatric neurosurgery. So in our study we used saline in PCIA/NCIA plus rescue medicine as our control group.
The regimens of PCIA or NCIA used the following formulas: Control (group C) included normal saline 100 ml, with a continuous background infusion of 2 ml/h, bolus 0.5 ml; Fentanyl (group F) was used with a loading dose of 0.5 μg/kg, a single bolus dose of 0.1–0.2 μg/kg, and a background dose 0.1–0.2 μg/k·h; Morphine (group M) was used with a loading dose of 50 μg/kg, a single bolus dose of 10–20 μg/kg, and a background dose of 10–20 μg/kg·h; while Tramadol (group T) was used with a loading dose of 500 μg/kg, a single bolus dose of 100–200 μg/kg, and a background dose of 100–400 μg/kg·h. The bolus locking time was 15 min. The total volume contained in the analgesia pump was adjusted to 100 ml with normal saline and 0.4 mg/kg of ondansetron. Patients would receive additional doses of ondansetron if they reported nausea or experienced vomiting. The type and dosed of medicines used in pump were converted to their respective milligram morphine equivalents (MME) using standardized conversion factors (1 mg of Fentanyl = 100 MME, 1 mg of tramadol = 0.1 MME) .
As a rescue medicine, ibuprofen suspension (20 mg/ml ibuprofen) was oral administered in the postoperative period in doses of 0.3 ml/kg for moderate pain (defined as a pain score ≥ 4 and < 7) within 48 postoperative hours. If the POPI is severe pain (defined as a pain score ≥ 7) or the first administration of ibuprofen couldn’t comfort the patient within 30 min, another rescue medicine intravenous morphine 0.02 mg/kg would be administered through peri vein. All rescue medicines were recorded.
Evaluation of pain intensity
The primary outcome of this study was postoperative pain intensity (POPI). According to the particular characteristics of each patient, we adopted different evaluation methods for POPI. Patients aged 1–6 years were evaluated by the Faces, Legs, Activity, Cry and Consolability Scale (FLACC, 0–10 scores) and the Wong-Baker Faces Scale (WBFS). For patients aged 7–12 years, both the numeric rating scale (NRS) and the Wong-Baker Faces Scale (WBFS) were used. The FLACC is a behavioral pain assessment tool that was developed to provide a simple and consistent evaluation method for these cases , while the WBFS is a self-reported pain assessment tool, currently considered the preferred alternative for pain assessment in children . The WBFS is comprised of a series of facial images, in which the face that depicts the most pain indicates the “worst pain imaginable” and the happiest face indicates “no pain” . The numeric rating scale (NRS) is a self-reported measure of pain intensity comprised of a line marked with numbers 0–10, in which 0 is “no pain” and 10 is the “worst pain imaginable” . POPI ratings were measured at 1, 2, 4, 16, 24, 36 and 48 h after surgery by the same observer. Moderate POPI was defined as a median pain score ≥ 4 and < 7 on the WBFS, FLACC or NRS scales. Severe pain was defined as a median pain score ≥ 7.
Randomization and blinding
Participants were randomly assigned 1:1:1:1 among four groups. The randomization schedule was generated by an independent investigator through a computerized random-number sequence. A specially selected nurse was informed of the group assignments and prepared the postoperative analgesia pumps according to the patients’ weights. Anesthesiologists were blinded to grouping information. Physicians responsible for postoperative follow-up were also blinded to the grouping.
Demographic data were recorded, including age, sex, height, weight, disease information, primary diagnosis, patients' medical history, and medications. Perioperative and anesthetic management information were also collected including: operation type; preoperative anesthetic medications; induction medications; intra-operative anesthetic medications; duration of surgery and anesthesia; and number of rescue medicine administrations.
The primary outcomes included pain scores at 1, 2, 4, 16, 24, 36 and 48 h after surgery. Secondary outcomes included the incidence of changes in consciousness, nausea, vomiting, pruritus, respiratory depression, and addition of perioperative acetaminophen. Nausea and vomiting were recorded if episodes of patient emesis were reported on nursing flow sheets, or if anti-emetic therapy was required. Respiratory depression was operationalized as a clinically significant decline in respiratory rate which required intervention, with SpO2 < 92%.
Sample size and statistical analysis
Continuous variables were described as median and interquartile range (IQR) or mean and standard deviation (SD), as appropriate. Categorical variables (sex, site of craniotomy) were presented as frequencies and percentages. The chi-square test was used for comparing proportions, and one-way analysis of variance (ANOVA) was used for comparing continuous variables between groups. Because the POPI of patients was ranked data, we used Kruskal-Wallis H-test to compare the differences of POPI among all groups. If P < 0.05, Dunnett’s T3 test was used to compare the differences of POPI between any two groups.
Our previous cohort study on POPI in pediatric craniotomy patients found that the incidence of moderate POPI in children to be approximately 45%. A final sample size was calculated based on the hypothesis that PCIA could reduce the incidence of moderate POPI at least 30%. A sample size of 36 patients was calculated to have a significance of 5% and a power of 80%, increased to 40 after considering a 10% maximal dropout rate.
Step-wise multivariate logistic regression was used to identify predictors for moderate POPI, with results presented as odds ratios (OR) and 95% confidence intervals (CI). Statistical analysis was performed using SPSS (version 22, BEIJING, Capital Medical University). All statistical tests were two-sided, and results were considered statistically significant when P < 0.05.