We did a prospective, controlled, assessor-blind, equivalence trial comparing neurodevelopmental outcomes at six months after surgery, in preschool children undergoing caries treatment under sevoflurane-based general anesthesia or awake-local anesthesia. The trial was done at the Stomatological Hospital of Chongqing Medical University, and the written consent obtained from parents or guardians. The study had been treated according to the declaration of Helsinki. It was registered with the Chinese Clinical Trial Registry (number ChiCTR1800015216), and the ethics committee approval of the Stomatological Hospital of Chongqing Medical University was obtained (number CQHS-IRB-2018-01).
Children’s neurodevelopment at six months after surgery was assessed by the Wechsler Preschool and Primary Scale of Intelligence, fourth edition (WPPSI-IV) Chinese version (CN). The WPPSI-IV (CN) is a test scale used to assess general intellectual function and neurocognitive development. It is mainly used in clinical and research fields, and it has a high-quality norm in China and high clinical validity. There are extensive academic literature and application experience about the WPPSI-IV (CN). The WPPSI-IV (CN) includes thirteen subtests, and the composite score includes the full-scale intelligence quotient (FSIQ), main index, and auxiliary index. The primary outcome for the analysis on a per-protocol basis was prespecified to be the FSIQ. The secondary outcomes for this analysis were selected main indexes, including Verbal Comprehension Index (VCI), Visual-Spatial Index (VSI), Fluid Reasoning Index (FRI), Working Memory Index (WMI), and Processing Speed Index (PSI), which are mainly used to evaluate the ability of knowledge expression and spoken language, visual-spatial information processing and vision-action coordination, fluid intelligence and inductive reasoning, visual working memory and attention, and cognitive flexibility and visual scan.
The sample size of this trial was calculated based on the FSIQ score. The mean of the FSIQ score in the reference population is 100, and the standard deviation is 15. Assuming a sample ratio of 1: 1, a significance level of 0.05, and a test power of 80%, the trial would need 308 patients. Enrolling roughly 340 patients would allow for 10% with dropping out. So, we planned to recruit 170 children receiving general anesthesia and 170 children receiving local anesthesia for dental procedures. The first assessment was performed at six months after surgery. The anesthetists, pediatricians, and parents were aware of group allocation, but the researchers who administered the neurofunctional assessments were not.
Inclusion criteria included healthy children less than 7 years old scheduled for caries treatment, and children classified as ASA I. According to the Frankl’s Behavior Rating Scale (FBRS), children with rating 1 (definitely negative behavior) received sevoflurane-based general anesthesia, and children with rating 2 to 4 (negative, positive, and definitely positive behavior) received awake-local anesthesia.
Exclusion criteria were any contraindication for anesthesia, previous exposure to general anesthesia, moderate to severe preterm infants (gestational age no more than 33 weeks), very low birth weight infant (birth weight less than 1500g), epileptic, any known neurological injury or developmental issues, other known diseases that might affect neurodevelopment, deaf-mute or blind, and any reason that might make follow-up difficult. Eligible children were recruited in the Department of Pediatric Dentistry or Anesthesiology of the Stomatological Hospital of Chongqing Medical University. During the research, children were excluded if they suffered brain injuries, underwent any other surgery, or failed to complete all procedures as protocol.
The awake-local anesthesia group received the local infiltration anesthesia after the behavior induction. Children under 4 years old were given 2% lidocaine hydrochloride injection (5ml: 0.1g, Southwest Pharmaceutical Co.; SFDA no.H50020038), with the total dose no more than 4 mg/Kg. Children aged 4 years and older were given 4% articaine hydrochloride and epinephrine tartrate injection (1.7ml: 68mg, Produits Dentaires Pierre Rolland; SFDA no.H20140732), with the maximum dosage not exceeding 5 mg/Kg.
The general anesthesia group only received sevoflurane (120ml, Shanghai Hengrui Pharmaceutical Co.; SFDA no.H20070172) for induction and maintenance. After induction with 5 L / min oxygen and 8% sevoflurane through the mask, the anesthetists chose and inserted the modified first-generation single-lumen laryngeal mask airway of the appropriate model. Anesthetists adjusted sevoflurane concentration during maintenance according to vital signs and Bispectral Index (the majority between 40 and 60 for the suitable depth of anesthesia), mostly 2.5% to 3.5% with a 2 L / min mixture of air and oxygen. In the whole process, the patients retained spontaneous breathing, and PetCO2 was usually maintained within 35 to 45 mmHg. Supplemental opioids, benzodiazepines, and other general anesthetics were not allowed, but local anesthetics were permitted to provide analgesia with the same dose as the local anesthesia group. There was postanesthesia care for 2 h after surgery. They were allowed to leave the hospital after the modified Aldrete score reached 10 points.
Data collection and measure
Before the operation, demographic data, pregnancy and birth details, and family structure were collected. During surgery, anesthetists recorded vital signs and perioperative adverse events. The patients were followed up by telephone on the day of surgery and the first day after surgery.
At six months after surgery, the WPPSI-IV (CN) was used to assess the neurodevelopment for two groups of children. It was to be done within one month after half a year after surgery. All children individually completed one-to-one with the qualified assessor. It took approximately 1.5 h for each child to complete the assessment. Parents were asked if children had been found physical abnormalities since caries treatment, and brief physical and neurological examinations were done for patients.
The hypothesis was that the FSIQ score is equivalent in children who have received general anesthesia or local anesthesia for caries treatment at six months after surgery. The equivalence margin was defined as five (1/3 SD), and a two one-sided test was performed with the 0.025 level of significance. Equivalence was predefined as the 95% CI of difference between the mean of the FSIQ score within -5 to +5. The secondary outcomes, VCI, VSI, FRI, WMI, and PSI, also have a mean of 100 and a standard deviation of 15. It is reasonable to assume that their equivalence margins are five. All CIs are two-sided.
The statistical analysis plan prespecified the age at evaluation (< 4 years old or ≥ 4 years old) as a subgroup analysis. Several predictor variables of primary outcome used in the regression model included anesthesia group, sex, gestational age at birth, birthweight, past medical histories of children, mother's abnormalities during pregnancy, mother's education, maternal age at delivery, perioperative adverse events, age at evaluation, and postoperative developmental disorders. In the general anesthesia group, the duration of sevoflurane exposure was used as a predictor variable and grouped (less than 120 min, 120 to 180 min, and more than 180 min) to observe the effect of different anesthesia duration on the primary outcome. All analyses were done in SPSS (version 25).