Authors: McCann ME et al
Lancet 2019; 393 (10172):664-677.
(P) For infants less than 60 weeks postmenstrual age, that were born at more than 26 weeks gestational age and undergoing inguinal herniorrhaphy, (I) effect of general anesthesia was compared with (C) awake regional anesthesia (O) on neurodevelopmental outcomes (T) over a period of 5 years.
- Design: multicenter, international, parallel-group, randomized, assessor-masked, controlled, equivalence trial
- Allocation: Concealed- Anesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors
- Blinding: Blinded
- Follow-up period: Infants were followed until 5 years of age
- Setting: 28 hospitals in seven countries- Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand
- Inclusion Criteria: infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were scheduled for inguinal herniorrhaphy
- Exclusion Criteria:
- Any contraindication for either anesthetic technique used in the study
- History of congenital heart disease requiring surgery or pharmacotherapy
- Mechanical ventilation immediately before surgery
- Known chromosomal abnormalities or other known acquired or congenital abnormalities that might affect neurodevelopment
- Previous exposure to volatile general anesthesia or benzodiazepines as a neonate or in the third trimester in utero
- Any known neurological injury such as cystic periventricular leukomalacia or grade three or four intraventricular hemorrhage
- Any social or geographical factor that might make follow-up difficult
- Use of a primary language at home in a region where neurodevelopmental tests were not available in that language
- Intervention: Awake-regional (AWR) group received a spinal, caudal, or combined caudal and spinal anesthetic, according to institutional preferences. Bupivacaine or levobupivacaine at a dose of 0·75–1 mg/kg was administered for spinal anesthesia. Caudal anesthesia was with 0·25% bupivacaine or levobupivacaine up to a total dose of 2·5 mg/kg. General anesthesia (GA) group received sevoflurane for induction and maintenance in a mix of air and oxygen. The concentration of sevoflurane, choice of airway device, ventilation technique, and use of neuromuscular blocking agents were left to the preference of the anesthetist.
- Outcomes: Neuropsychological assessments were to be done within 4 months of the child turning 5 years of age
- Primary outcome: Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III) full-scale intelligence quotient (FSIQ) score
- Secondary outcomes: Selected NEuroPSYchological (NEPSY-II) subtests to assess attention and executive function; the Wechsler Individual Achievement Test, second edition (WIAT-II),orthe BVN (the Italian equivalent of the WIAT- II); selected subtests of the Children’s Memory Scale (CMS); the global executive composite of the Behaviour Rating Inventory of Executive Function, Preschool version (BRIEF-P); the Adaptive Behaviour Assessment System, second edition (ABAS-II); and the Child Behaviour Checklist caregiver questionnaire (CBCL)
- Analysis and sample size: The authors hypothesized that the WPPSI-III FSIQ score at age 5 years would be equivalent between study groups.
- Outcomes were analyzed on a per-protocol basis to ensure a conservative estimate of the treatment effect in the direction of non-equivalence. Equivalence was defined a priori as the 95% CI of the difference in means of the FSIQ lying within –5 and +5 IQ points. Sample size assumed a 90% chance that the 95% CI would exclude a difference of more than 5 points. Accounting for a 10% loss to follow-up and a 10% rate of major protocol violations, about 720 participants were needed.
- Multiple imputations were done under a multivariate normal distribution to impute missing outcome data in the primary analysis of all outcomes, with a sensitivity analysis done on only complete cases.
- This study screened 4023 infants, enrolling 722 participants. 5-year assessment was done for 447 patients, 205 of which received awake-regional anesthesia and 242 received general anesthesia. The variables used in the multiple imputation models included baseline, post-randomization, 2-year cognitive variables and 5-year outcome variables.
- Patient follow-up: Of the enrolled infants, 447 infants were analyzed for difference in neurodevelopmental outcomes based on type of anesthesia at the end of 5 years.
There was no difference in baseline demographics, pregnancy and birth details, familial demographics as well as anesthesia variables (i.e. need for fluid bolus for hypotension, duration of surgery and sevoflurane exposure, significant postoperative apnoea, use of rescue IV glucose or vasoactive drugs). The study population had a male preponderence (84% participants were males), given the procedure performed. The chronological age at surgery was 68.9 (mean 30.8) days vs 71.1 (mean 31.7) days and weight of child at surgery was 4.2 kg (1.1) vs 4.3 (1.1) kg in AWR and GA groups respectively
The mean duration of general anesthesia was 54 mins (IQR 41-70)
Infants that received sevoflurane required more fluid boluses (17% vs 5%) and vasoactive medications (5% vs 1%).
19% ( 69 of 361) infants in AWR group had some exposure to the genreal anesthetics due to required deviation during surgery when optimal sedation or pain control could not be acheived
The authors conclude that less than 1 h of general anesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anesthesia in a predominantly male study population.