Long-term outcomes of early exposure to repeated general anaesthesia in children with cystic fibrosis (CF-GAIN)
A multicentre, open-label, randomised controlled phase 4 trial
The Lancet
Submitted February 2025 by Dr Nicole Wylie
Read by 41 Journal Watch subscribers
Summary -
Study Type:
The initial trial was a prospective, open-label, unblinded, randomised and multi-centre trial designed to look at the entirely different clinical question of pulmonary and nutritional outcomes. This study is an opportunistic ‘extension study’ that takes advantage of two prospectively gathered cohorts from the initial trial to serendipitously address one of the currently most pressing questions in paediatric anaesthesia: if a single, short general anaesthetic in the infant population demonstrates no significant differences in neurocognitive outcomes (as per the robust GAS trial), then do repeated and/or cumulative exposures to GAs in the under-two age group pose a cause for concern?
Methods:
This (CF-GAIN) is an opportunistic post-hoc analysis of data generated in the ACFBAL trial, which was powered to detect differences in pulmonary and nutritional outcomes at 5 years in patients with congenitally-identified cystic fibrosis who were randomised to either broncho-alveolar lavage (BAL) directed therapy or standard care. Importantly (for the question of confounders in the CF-GAIN study) there were no significant differences between these groups.
This initial trial generated two comparable cohorts, one of whom had reliably received repeated short general anaesthetics by two years of age (52 patients), and the other of whom had not (45 patients).
Exclusions criteria included:
- general anaesthesia prior to ACFBAL randomisation
- delivery via GA-C-Section
- underlying genetic conditions associated with neurocognitive issues.
Confounders such as parental educational attainment, socio-economic disadvantage, and school delay were also examined.
The initial methodology underwent a change of protocol: the extensive battery of testing was deemed too significant a burden on patients and family, so validated but shorter testing panels were used (NEPSY-II, CPT-II, and WIS 4th ed), along with MRI brain (standardised scanning protocol). A subjective quality of life score specific to CF patients was also included. Psychologists were given a manual on the testing protocol, and families asked to not discuss which branch of the ACFBAL study they had been in.
For examination of any potential dose effect, GAs from the end of the ACFBAL up to 6 years of age were assessed.
Findings:
1. At the end of the ACFBAL trial, all of the BAL-therapy group had had multiple exposures (median 6, IQR 4-9.5); 64% (29/45) had median 2 (IQR 1-4) exposures.
2. The cumulative exposure in the first two years in the BAL group was 36 min (IQR 26-84), and in the standard care group 0min (IQR 0-0).
3. The cumulative exposure at the end of the trial (five years old) was 180 min (IQR 140-285) and standard group 48 min (IQR 30-122)
4. There were no differences between the two groups of any neurocognitive or behavioural outcomes.
5. There was no indication of a cumulative effect of GA on neurocognitive or behavioural outcomes
- a. 16% (8/49) in the BAL-group vs 2% (1/45) in the standard treatment had been held back a year in school.
- b. HOWEVER subgroup analysis found those held back were the same age as their school group peers rather than being older, suggesting maturity rather than impairment as an aetiology.
6. MRI findings – there was ‘no convincing evidence of structural differences on MRI between those receiving early GA exposures and those in standard-care group. The authors note that average grey matter volume was slightly lower in the GA group and body of the corpus collosum was slightly higher, but the study was underpowered to exclude these changes occurring by chance.
Take Home Messages -
Limitations:
1. This trial was done in children with CF, by definition an underlying medical condition with potential for significant impact on those affected.
2. 42% of the original ACFBAL group were lost to follow-up. However, an analysis of summary characteristics of the populations show no significant differences.
3. Data relating to cumulative general anaesthesia time was not prospectively collected, and so was reliant on retrospective collection.
4. The ACFBAL trial protocol used sevoflurane, but other agents were used. In 24 of 812 GAs, the agent(s) used were not recorded. It is unclear what, if any, impact the choice of agent may have. Cumulative exposure time was able to be assessed in 630 (78%) of GAs.
5. The study was designed to assess different outcomes; a priori powering for subtle neurocognitive changes is unclear.
Applicability:
While this study is of a population with a known pre-existing illness that may limit its generalisability to ‘well’ children, a lot of patients in whom early, cumulative exposure to GAs is required by the nature of their illnesses raises concerns about their potential vulnerability makes it an attractive study group.
Pending Questions:
This study, while encouraging, is hampered by the retrospective nature of its data collection and lack of a priori power design. We await the outcomes of the T-REX trial to further elucidate this question.
