No Answer to an Unanswerable Question: Does Cumulative Anesthetic Agent Exposure Influence Neurobehavioral Outcome in Children with CHD?
James DiNardo, Viviane Nasr, Lindsey Loveland Baptist, Susan Nicolson
Today’s PAAD was previously posted on August 7 when our cardiac team reviewed the article as an epub ahead of print. In this reposting, I am also including the full citation for the article and its accompanying editorial which was unavailable at the time of our previous PAAD posting.
Because developmental anesthetic neurotoxicity has bedeviled and divided our community for nearly 2 decades, today’s article and editorial provides reassurance that prolonged administration of most anesthetics is safe in terms of neurodevelopmental outcomes. I would urge you to read both. Myron Yaster MD
Editiorial
Ing C, Vutskits L. Developmental Anesthesia Neurotoxicity: Lessons from the Heart. Anesthesiology. 2023 Oct 1;139(4):371-373. PMID: 37698431
Original article
Simpao AF, Randazzo IR, Chittams JL, Burnham N, Gerdes M, Bernbaum JC, Walker T, Imsdahl S, DeWitt AG, Zackai EH, Gaynor JW, Loepke AW. Anesthesia and Sedation Exposure and Neurodevelopmental Outcomes in Infants Undergoing Congenital Cardiac Surgery: A Retrospective Cohort Study. .Anesthesiology. 2023 Oct 1;139(4):393-404. doi: 10.1097/ALN.0000000000004684. PMID: 37440275
The potential long-term deleterious effects on brain development of repetitive anesthetic and sedative agent exposures in young children has been a source of concern and the target of both basic scientific and clinical research for over 20 years. Children with CHD have been deemed to particularly vulnerable in this regard both because there are myriad other factors unique to them that affect neurobehavioral development and because they are likely to have multiple, lengthy exposures to anesthetic and sedation medications.
Neurodevelopmental impairment is common among children with CHD with more than half of those with complex CHD demonstrating some form of neurodevelopmental, neurocognitive, and psychosocial dysfunction that impacts long-term quality of life and often requires specialized care.1 Twenty five percent of newborns with complex CHD have white matter injury (WMI) before their first cardiac operation and 45% of children with CHD have genetic abnormalities many of which are associated with neurodevelopmental deficiencies. It is well established that white and gray matter development is also disrupted prenatally in fetuses with CHD. In children with CHD abnormal brain growth begins in mid-gestation. Children with lesions such as hypoplastic left heart syndrome or D-transposition of the great arteries (d-TGA) where there is reduced fetal cerebral oxygen and substrate delivery are at particular risk. After birth, term infants with hypoplastic left heart syndrome or d-TGA have brain maturation similar to that in healthy neonates who are 1 month younger in gestational age.2, 3 A full accounting of the potential influences on neurobehavior outcome in child with CHD is summarized in the Figure.
Presented here is a good faith, meticulous effort by an established research team to describe the association between neurodevelopmental outcomes and cumulative inpatient exposure to sedative and anesthetic medications during the first 18 months of life in children with congenital heart disease.4 The stated primary hypothesis was that greater exposure to sedation and anesthesia in infants undergoing cardiac surgery would be associated with lower neurodevelopmental scores at 18-month follow-up. The retrospective cohort study was a secondary analysis of a prospective observational study evaluating environmental exposures and neurodevelopmental outcomes in pediatric patients with congenital heart disease undergoing surgery at Children’s Hospital of Philadelphia.4
Cumulative minimum alveolar concentration hours of exposure to volatile anesthetic agents and all operating room and intensive care unit exposures to sedative and anesthesia medications were collected prior to administration of Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 18-months of age. The study cohort included 41 (37%) single-ventricle and 69 (63%) two-ventricle patients. Exposures to volatile anesthetic agents, opioids, benzodiazepines and dexmedetomidine were not associated with abnormal Bayley-III scores. At 18-month follow-up, after adjusting for confounders, each mg/kg increase in ketamine exposure was associated with a 0.34 (95%CI: -0.64, -0.05) point decrease in Bayley-III Motor scores, P = 0.024.
So where does this leave us? Unfortunately, the conclusions we can draw from this investigation are subject to the same limitations encountered in previous attempts5, 6 to address this question, small sample sizes and more importantly a highly unfavorable signal to noise ratio. Signal to noise ratio is defined here as: (impact of anesthetic and sedative agent exposure on the primary outcome) /(impact of known and unknow covariates on the primary outcome) where noise is orders of magnitude greater than the signal rendering accurate measurement of the signal impossible. A final important limitation here is the failure of the analysis to adjust for or to conduct sensitivity analysis to determine the effect of the covariate, environment exposure, found to influence neurobehavioral outcome in the original dataset.
In the absence of a huge, extremely complex controlled randomized trial to isolate the weak signal generated by anesthesia and sedative agent exposures against the background of intense noise we should continue to make decisions on the choice of agents we use based on our best assessment of the patients’ perioperative recovery trajectory and well-defined hemodynamic goals.
What are your thoughts? Send to Myron who will post in the Friday Reader Response.
Figure. Risk Factors for Neurologic and Neurodevelopmental Abnormalities. Schematic representation of prenatal, perioperative, and social/environmental factors that contribute to neurodevelopmental disabilities (ND) in CHD. Reference #1
References
1. Ortinau CM, Smyser CD, Arthur L, et al. Optimizing Neurodevelopmental Outcomes in Neonates With Congenital Heart Disease. Pediatrics. Nov 1 2022;150(Suppl 2)doi:10.1542/peds.2022-056415L
2. Ortinau CM, Shimony JS. The Congenital Heart Disease Brain: Prenatal Considerations for Perioperative Neurocritical Care. Pediatric neurology. Jul 2020;108:23-30. doi:10.1016/j.pediatrneurol.2020.01.002
3. Newburger JW. Reducing Perioperative Brain Injury in Congenital Heart Disease: A Ray of Hope. Journal of the American College of Cardiology. Jan 24 2023;81(3):267-269. doi:10.1016/j.jacc.2022.11.027
4. Gaynor JW, Burnham NB, Ittenbach RF, et al. Childhood exposures to environmental chemicals and neurodevelopmental outcomes in congenital heart disease. PloS one. 2022;17(11):e0277611. doi:10.1371/journal.pone.0277611
5. Diaz LK, Gaynor JW, Koh SJ, et al. Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome. The Journal of thoracic and cardiovascular surgery. Aug 2016;152(2):482-9. doi:10.1016/j.jtcvs.2016.03.095
6. Andropoulos DB, Ahmad HB, Haq T, et al. The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. Paediatric anaesthesia. Mar 2014;24(3):266-74. doi:10.1111/pan.12350