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The Debate on Pediatric Anesthesia and Child Development

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In February 2019, the New York Times published an article entitled, “Having Anesthesia Once as a Baby Does Not Cause Learning Disabilities, New Research Shows”1. The article unveiled the results of a randomly controlled trial that compared neural development between infants that were exposed to anesthesia, and the control cohort of infants who had no such exposure. This study conclusively found that there were no significant neurodevelopment differences among the cohort. In producing such results, the New York Times contributed to a larger debate in the surgical and anesthesia services community on the use of pediatric anesthesia. Over the past decade, multiple conflicting reports have emerged regarding the effects of administering anesthesia to pediatric patients on neurological development. The topic is oft-debated in the academic literature. A brief summary of important research to-date is useful for evaluating this question and deciding treatment plans for the pediatric population.

The theory suggesting that pediatric anesthesia administration could potentially impart negative effects on patients was early introduced on by results from animal studies. In 2003, Dr. Jevtovic-Todorovic and her research team discovered that exposure to nitrous oxide, isoflurane, and midazolam led to significant neurodevelopmental effects in neonatal rats2. In this study, the exposure to anesthesia agents was designed to mimic that of percentages utilized in surgery. Furthermore, the length of exposure similarly matched an average surgery, approximately 6 hours, in order to include time as a relevant factor. The results revealed that the neonatal rats exposed to anesthesia suffered apoptotic neurodegeneration, impaired memory and learning, and a decrease in hippocampal function. These specific and impactful results served as a cause for concern, as animal models often preempt human subjects’ trials. The result of this animal study therefore spurred debate among the anesthesiology and surgical academic fields as to the relevance of the results, as well as the possible mechanisms by which these effects occur.

Of note, Block et al revealed in a 2012 study that early exposure to anesthesia, defined in this study as before one year of age, results in a significant decrease of white matter in the brain3. The longitudinal study followed two cohorts, the anesthesia exposure cohort and the control, recording intellectual capability as measured by academic achievement over a decade. The study subjects also underwent significant neuro-imaging, including MRI. In this study, subjects who had anesthesia as infants reported a 4% decrease in white matter content compared to the control. For reference, white matter is linked with neural communications, as well as learning and neuronal function4.

In the same wave that academic research commenced a focus on these topics, national healthcare policy similarly followed suit. The U.S. Food and Drug Administration (FDA) has released multiple bulletins detailing that the agency warned against administering anesthesia to patients less than three years of age5. If anesthesia is necessary, the FDA recommended that the procedure be less than three hours in totality. These guidelines were readily adopted in multiple healthcare institutions across the States, according to FDA data.

However, in recent years, human subject studies have provided results in contrast with earlier research on this topic, thus suggesting that previous results may have been based on confounding factors. The Mayo Anesthesia Safety in Kids study, results published in 2018, compared three cohorts of pediatric patients and followed the subjects for up to 20 years post-exposure6. The cohorts included control of unexposed patients, patients who were exposed to anesthesia once, and patients who were exposed to anesthesia multiple times. The results showed that exposure of anesthesia before 3 years of age was not associated with negative impacts with regards to IQ and neuropsychological assessment. These results were supported by a recent large-scale study, which examined the effect of anesthesia exposure for more than 10,000 study subjects over time and found that exposure to anesthesia was not associated with any neurocognitive deficits7. Therefore, current studies clearly suggest that the previous links to neurological defects are not indicative of causality and are likely due to confounding or external biological and environmental factors.

Researchers in the anesthesia and surgical space will continue to study pediatric anesthesia and its specific effects until the advent of a clinically accepted definition. However, the recent press attributed to this topic underscores the importance of focusing clinical care on pediatric and other vulnerable populations, for anesthesia providers, researchers, and policy-makers alike.

1 Klass, Perri. “Having Anesthesia Once as a Baby Does Not Cause Learning Disabilities, New Research Shows.” The New York Times, The New York Times, 18 Feb. 2019,

2 Jevtovic-Todorovic, V, et al. “Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits.” Journal of Neurosurgical Anesthesiology, vol. 15, no. 3, 1 Feb. 2003, pp. 295–296., doi:10.1097/00008506-200307000-00029.

3 Block, Robert I., et al. “Are Anesthesia and Surgery During Infancy Associated With Altered Academic Performance During Childhood?” Survey of Anesthesiology, vol. 57, no. 2, 2013, p. 80., doi:10.1097/sa.0b013e318287d938.

4 U.S. National Library of Medicine. “White Matter of the Brain: MedlinePlus Medical Encyclopedia.” MedlinePlus, U.S. National Library of Medicine,

5 Center for Drug Evaluation and Research. “Drug Safety and Availability – FDA Drug Safety Communication: FDA Review Results in New Warnings about Using General Anesthetics and Sedation Drugs in Young Children and Pregnant Women.” U S Food and Drug Administration Home Page, Center for Drug Evaluation and Research,

6 Warner, David O, et al. “Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study.” Anesthesiology, U.S. National Library of Medicine, July 2018,

7 O’Leary, James D., et al. “Influence of Surgical Procedures and General Anesthesia on Child Development Before Primary School Entry Among Matched Sibling Pairs.” JAMA Pediatrics, vol. 173, no. 1, 2019, p. 29., doi:10.1001/jamapediatrics.2018.3662.

Multi-modal Pain Regimens May Affect Post-Operative Pain Control for Patients

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In October 2017, the Department of Health and Human Services officially declared that the opioid crisis constituted a nationwide public health emergency1. The recent recognition of ubiquitous over-prescription of opioids from physicians and policy-makers concurs with this statement. Opioid monotherapy may be considered the standard of care at multiple healthcare institutions given its high magnitude analgesic qualities. However, as noted in the public health emergency declaration, opioid monotherapy is associated with several adverse effects, from respiratory depression to delirium, that may impede post-operative recovery. In response to this scenario, it is introduced that multi-modal pain regimens may affect post-operative pain control for patients, serving as an alternative solution.

Multi-modal pain regimens, also known as multi-modal analgesia, are comprised of two or more pain relief treatments administered simultaneously. The treatments may be pharmacologic agents, such as opioids, anticonvulsants, and benzodiazepines, or non-pharmacologic treatments such as applied heat or ice, massage, or electroanalgesia2. In a broad sense, the appropriate multi-modal pain regimen is decided by anesthesiologists, surgeons and other perioperative physicians. It may vary depending on the patient’s health history and the specific surgical operation’s outcomes. Furthermore, a multi-modal approach is endorsed by leaders in anesthesia and pain management. The American Pain Society published a set of guidelines for post-surgical pain management, including dedicated algorithms for a multi-modal approach3. The Society specifically determined that acetaminophen and/or non-steroidal anti-inflammatory drugs should be included as part of a multi-modal approach. This set of guidelines was further endorsed by the American Society for Regional Anesthesia, a professional society for clinicians and researchers. Multi-modal treatments will range in terms of the combinations of treatments, and effective algorithms continue to be studied.

Recently, research has suggested that a multi-modal analgesia approach delivered to women undergoing Cesarean section (C-section) has a significant effect on patient post-operative opioid use, as well as length of stay. Maternal and pregnant populations are oft understudied in academic medical research, particularly in cases of sensitive anesthesia and pain management services. To respond to this gap in the literature, researchers from the University of Illinois Hospital and Health Sciences System developed a multi-modal approach for C-section mothers4. In the intervention cohort, mothers were administered a combination of ketorolac, gabapentin, and/or acetaminophen medications depending on the patient’s pain designation score. A small subset of patients who reported significantly higher pain scores were treated with an opioid in combination with other drugs. The control was conventional care opioid prescriptions. In the study, the intervention cohort reported a greater than 50% decrease in number of opioid tablets prescribed at discharge. For reference, 89% of control patients were prescribed opioids at discharge, compared to 32.5% of intervention cohort patients. In addition, the intervention cohort reported a decrease in length of stay, which implies positive connotations towards the patient’s recovery. Long-term effects of the patients in this study will continue to be studied, yet the current results point to a promising future of non-opioid or minimized opioid multi-modal regimens for post-C-section patients.

Developing research-supported, modern regimens to treat patients remains a high priority for clinicians and scientists in anesthesia and pain management. Multi-modal analgesia represents a significant opportunity to improve post-operative acute care in sensitive populations, further contributing to clinical efficacy as well as public health.

1. U.S. Department of Health and Human Services. “HHS Acting Secretary Declares Public Health Emergency to Address National Opioid Crisis.”, US Department of Health and Human Services, 23 May 2018,

2. Helander, Erik M., et al. “Multi-modal Analgesia, Current Concepts, and Acute Pain Considerations.” Current Pain and Headache Reports, vol. 21, no. 1, 2017, doi:10.1007/s11916-017-0607-y.

3. Chou R, Gordon DB, de Leon-Casasola, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17:131-157.

4. Khudeira, Zahra. “Use of Multi-modal Analgesia in Women Post-Cesarean Section: From Innovation to Bedside.” ICHP: Journal of the Illinois Council of Health-System , vol. 44, no. 08, 2018.