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Original Investigation
June 20, 2019

Association Between Anesthesia Exposure and Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia

Author Affiliations
  • 1Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
  • 2Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, Tennessee
  • 3Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee
  • 4Department of Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, Tennessee
  • 5Department of Psychology, St Jude Children's Research Hospital, Memphis, Tennessee
  • 6Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
JAMA Oncol. 2019;5(10):1456-1463. doi:10.1001/jamaoncol.2019.1094
Key Points

Question  Do multiple exposures to general anesthesia in children have a negative association with neurocognitive function and brain imaging?

Findings  In this cohort study of 212 eligible survivors of childhood acute lymphoblastic leukemia treated at a single institution between 2000 and 2010 who underwent 5699 exposures to general anesthesia, higher cumulative doses of fluranes and propofol and longer anesthesia duration significantly contributed to neurocognitive impairment and neuroimaging abnormalities at a median of 7.52 years since diagnosis, beyond the known results of neurotoxic chemotherapies.

Meaning  In pediatric populations with chronic health conditions who undergo multiple anesthesia exposures, limiting exposure to general anesthesia may be warranted.


Importance  Limited studies have reported associations between anesthesia and neurocognitive and neuroimaging outcomes, particularly in pediatric patients who undergo multiple exposures to anesthesia as part of chronic disease management.

Objective  To investigate whether general anesthesia is associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia.

Design, Setting, and Participants  A cohort study of 212 survivors of childhood acute lymphoblastic leukemia who received treatment between July 7, 2000, and November 3, 2010, and follow-up at a mean (SD) of 7.7 (1.7) years post diagnosis, was conducted at an academic medical center. Of 301 survivors who were alive and eligible for participation, 217 individuals (72.1%) agreed to participate in long-term follow-up. Data analysis was performed from August 23, 2017, to May 3, 2018.

Exposures  For 5699 anesthesia procedures, data on duration and cumulative doses of all anesthetics, sedatives, analgesics, anxiolytics, and neuromuscular blockers were abstracted, along with cumulative doses of high-dose intravenous methotrexate and number of triple intrathecal chemotherapy treatments.

Main Outcomes and Measures  Neurocognitive measures of attention, processing speed, executive function, and intelligence were examined. Brain volumes, cortical thickness, and diffusion tensor imaging of the whole brain, corpus callosum, frontal lobes, and parietal lobes were evaluated.

Results  Of the 217 study participants, 212 were included in both neurocognitive and brain imaging analysis. Of these, 105 were female (49.5%); mean (SD) age at diagnosis was 14.36 (4.79) years; time since diagnosis was 7.7 (1.7) years. Adjusting for chemotherapy doses and age at diagnosis, neurocognitive impairment was associated with higher propofol cumulative dose (relative risk [RR], 1.40 per 100 mg/kg; 95% CI, 1.11-1.75), flurane exposure (RR, 1.10 per exposure; 95% CI, 1.01-1.21), and longer anesthesia duration (RR, 1.03 per cumulative hour; 95% CI, 1.00-1.06). Slower processing speed was associated with higher propofol dose (estimate [est], −0.30; P = .04), greater number of exposures to fluranes (est, −0.14; P = .01), and longer anesthesia duration (est, −0.04; P = .003). Higher corpus callosum white matter diffusivity was associated with dose of propofol (est, 2.55; P = .01) and duration of anesthesia (est, 2.40; P = .02). Processing speed was significantly correlated with corpus callosum diffusivity (r = −0.26, P < .001).

Conclusions and Relevance  Higher cumulative anesthesia exposure and duration may be associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia, beyond the known outcomes associated with neurotoxic chemotherapies. Anesthesia exposures should be limited in pediatric populations with chronic health conditions who undergo multiple medical procedures.