The effect of sevoflurane anesthesia for dental procedure on neurocognition in children: a prospective, equivalence, controlled trial

We did a prospective, controlled, assessor-blind, equivalence trial comparing neurocognitive outcomes at 6 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 was 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 neurocognitive function 6 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 13 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% of 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 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 1500 g), 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 (5 ml: 0.1 g, 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 (1.7 ml: 68 mg, Produits Dentaires Pierre Rolland; SFDA no.H20140732), with the maximum dosage not exceeding 5 mg/Kg.

The general anesthesia group only received sevoflurane (120 ml, 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.

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 6 months after surgery, the WPPSI-IV (CN) was used to assess the neurocognitive function for two groups of children. It was to be done within 1 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 6 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).

Between Feb 1, 2019, and Aug 31, 2019, 1681 children were screened for eligibility, and 340 patients were recruited. After three withdrawal of consent by parents (pre-surgery), the intent-to-treat analysis included 168 children in the general anesthesia group and 169 children in the local anesthesia group. Thirty-one participants with surgery being canceled or protocol violations were excluded, and 150 patients in the general anesthesia completed the surgery and 156 in the local anesthesia group.

Follow-up was from Aug 1, 2019, to Mar 22, 2020. Twenty-eight families were lost to follow-up or withdrew consent, and one child was injured by falling from a height. In the per-protocol analysis, the WPPSI-IV (CN) was complete for 129 in the general anesthesia group and 144 in the local anesthesia group (Fig. 1).

Demographic data at baseline and anesthesia details are shown in Table 1. There were 63 boys (49%) in the general anesthesia group and 77 boys (53%) in the local anesthesia group. The age at surgery was from 2.5 to 6.5 years old. Among all participants, 9 mothers had mild abnormalities during pregnancy, and 12 children had a past medical history. The median duration of sevoflurane use was 130 min (110 to 160). The only adverse event during the perioperative period in the general anesthesia group was related to respiratory complications (two cases of slight laryngospasm), and one case of the local anesthetic adverse reaction occurred in the local anesthesia group.

Non-scale measurements at 6 months after surgery are shown in Table 2. There were 16 children less than 4 years old in the general anesthesia group and 9 children in the local anesthesia group. After surgery, no child had a diagnosis of febrile convulsion, epileptic seizure, or cerebral palsy, nor did they fail to complete WPPSI-IV (CN) due to developmental issues or behavioral disorders. The neurological examinations of all children were normal.

The scores of FSIQ and main indexes (VCI, VSI, FRI, WMI, and PSI) in the WPPSI-IV (CN) of the two groups were shown in Table 3. For the FSIQ score, the mean was 103·12 (SD 8.94) in the general anesthesia group and 103·58 (8.40) in the local anesthesia group. We noted evidence for equivalence between groups in means (mean difference for local anesthesia minus general anesthesia 0.46, 95% CI − 2.35 to 1.61). There was also evidence for equivalence in the scores of VCI, VSI, FRI, WMI, and PSI between groups. The upper and lower limits of the 95% CIs were well inside the prespecified equivalence margin of five in all analyses.

In the subgroup analysis, the FSIQ score between groups was equivalent in the age group less than 4 years old. It was the same in the age group older than 4 years. There was no significant difference between the two age groups in the general anesthesia group and the local anesthesia group (p > 0.05). For the secondary outcomes, in the age subgroup of younger than 4 years, the VSI and WMI scores were not found to be equivalent between groups; in the age subgroup of older than 4 years, the VSI score was not equivalent (Table 4).

In the unary linear regression analysis, it was found that the anesthesia group, sex, preterm, birthweight, past medical histories of children, mother’s pregnancy disease, maternal age at delivery, perioperative adverse events, and age at evaluation could not significantly affect the primary outcome (p > 0.05). Only the significance level of maternal education was less than 0.05 (b = 1.94, adjusted R-squared = 1.60%), which could affect the FSIQ score (Table 5). And from Table 1 we can see that there was no significant difference in the distribution of mother’s education between the two groups of children. However, after incorporating all the above predefined predictor variables into the multiple linear regression analysis, it was found that the overall significance level was above 0.05, and the significance of the mother’s education was also similar. It may be that although the mother’s education could affect the outcome in the unary linear regression, the influence was relatively small. When it was included in the multiple linear regression, the influence of maternal education was concealed due to the interaction between the predictor variables. In the general anesthesia group, the duration of sevoflurane exposure did not significantly affect the primary outcome (p = 0.860), and there was no significant difference in FSIQ score between groups (less than 120 min, 120 to 180 min, and more than 180 min) of different anesthesia durations (p = 0.079). (as shown in Fig. 2).