We read with interest Banerjee et al’s work describing the long term neurocognitive outcomes of childhood acute lymphoblastic leukemia.1 The adult sequelae of pediatric major illness is a subject of substantial interest as short-term therapeutic outcomes continue to improve and the number of adult survivors of major illness increase.
As observational researchers within the field of anesthesiology, in reading the manuscript we were left with three questions::
Firstly, does the cohort, after adjustment, vary only by anesthesia exposure? As the authors note, anesthesia care was commonly provided for a full range of procedures. Thus it seems likely that anesthesia exposure is highly co-linear with extent of treatment. While the authors adjusted for methotrexate exposure and intrathecal administration as recommended by current guidelines2, the number and nature of the treatment exposures described in this study appear highly variable. There likely are non-oncologic factors which also impact these outcomes. Taken collectively, factors which may influence long-term cognitive trajectories appear incompletely accounted for.
Secondly, why is the incidence of significant cognitive deficit so high? A robust debate exists on the long term outcomes of children who have been exposed to anesthesia care at a young age.3 The described 42% incidence of 3 or more psychometric tests at 2 standard deviations below expected values appears to be beyond what contemporary anesthetic literature describes.4
Thirdly, what is the biological plausibility of the relationship? The authors conclude that exposure to propofol and volatile anesthetic agents are associated with the described outcome. Pre-clinical work has linked these agents, alongside ketamine to histological changes in animal models. However, animal models have not clearly translated into clinical practice.3,5 The authors’ discussion of this phenomena appears incomplete. Limited consideration has been offered to the possibility of direct or mediated neurotoxicity of the cytotoxic agents routinely and variably employed in the treatment protocols described in this study.
While we agree that it is desirable to seek non-pharmacologic methods of achieving patient comfort, in light of the questions noted above, we believe the study findings should be considered as hypothesis-generating, and authors’ stated conclusions to limit anesthetic exposures in order to reduce neurocognitive impairment and neuroimaging abnormalities are premature. We look forward to further work which validates the hypotheses emerging from this study.
Acknowledgments
Sources of Financial Support:
All work and partial funding attributed to the Department of Anesthesiology, University of Michigan Medical School (Ann Arbor, Michigan, USA).
Dr Mathis is supported National Heart, Lung and Blood Institute of the National Institutes of Health under award number K01HL141701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflicts of Interest: None
References:
- 1.Banerjee P, Rossi MG, Anghelescu DL, et al. Association Between Anesthesia Exposure and Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia. JAMA Oncol. June 2019. doi: 10.1001/jamaoncol.2019.1094 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol. 2004;22(24):4979–4990. [DOI] [PubMed] [Google Scholar]
- 3.Davidson AJ, Sun LS. Clinical Evidence for Any Effect of Anesthesia on the Developing Brain. Anesthesiology. 2018;128(4):840–853. [DOI] [PubMed] [Google Scholar]
- 4.Disma N, O’Leary JD, Loepke AW, et al. Anesthesia and the developing brain: A way forward for laboratory and clinical research. Paediatr Anaesth. 2018;28(9):758–763. [DOI] [PubMed] [Google Scholar]
- 5.Jevtovic-Todorovic V Exposure of Developing Brain to General Anesthesia: What Is the Animal Evidence? Anesthesiology. 2018;128(4):832–839. [DOI] [PMC free article] [PubMed] [Google Scholar]