Why is this important? Risk of Neurotoxicity in Children from General Anesthesia Marisa Earley, MD Pediatric Otolaryngology UTHSCSA Department of Otolaryngology Head and Neck Surgery September 30, 2016 Image from: Chen, P. Bringing Doctors to the Dying Patient s Bedside. The Human Side of Doctor-Patient Relationships. NYTimes. 2010 June. http://mobile.nytimes.com/2010/06/03/health/03chen. html?_r=0 It s not just the surgeries More informed parents, families and patients 4 Disclosures Marisa Earley, MD has no relationships with commercial companies to disclose Some of the information in this presentation has been submitted for publication in Laryngoscope 2 Learning Objectives At the end of this presentation the participant will be able to: Discuss findings from otolaryngologic literature in regards to discussion of risk of neurotoxicity in children undergoing general anesthesia. Describe current recommendations and controversies regarding neurodevelopmental risks from pediatric anesthesia. List resources available to educate both providers and parents regarding the risks from general anesthesia in children 3 1
Who s affected? Search terms 2010 Census: 20 million children in US < 5 years 10% undergo general anesthesia/deep sedation each year Over 1.5 million ambulatory pediatric ENT procedures performed annually Does not include inpatient or urgent surgeries or imaging Bhattacharyya N. Ambulatory pediatric otolaryngologic procedures in the United States: characteristics and perioperative safety. Laryngoscope. 2010 Apr;120(4):821-5. 7 10 Why I became interested Flow Diagram Parent: So how safe is anesthesia? What do I need to know? Anesthesiologist: It s safer than driving a car! Me:??? 8 Assessing Awareness Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J. 2009 Jun;26(2):91-108 9 12 2
16 Why ENT is Unique Role of hearing loss in learning and language development Role of OSA in neurodevelopmental problems Syndromic children Emergent cases 14 Strategies for Mitigating Anesthesia Related NeuroToxicity in Tots SMART Tots 3
DOI: http://dx.doi.org/10.1002/brb3.514 CHANGE GEARS So what does the anesthesia research show? General anesthetics given during peak synaptogenesis causes cell death, impaired neurogenesis and subsequent cognitive impairment 2016: Early life single Sevoflurane exposure Mice pups on post natal day 7 were administered 2.3% Sevo for 2 hours compared to controls and were assessed for cognition and neuropsychiatric like behavioral changes at 1 5 months of age Exposed mice had a deficit in learning and memory as well as social interaction deficits in peri adolescense and adulthood 19 Lin D, et al. Early-life single-episode sevoflurane exposure impairs social behavior and cognition later in life. Brain and behavior, 2016;6(9): DOI: 10.1002/brb3.514. 22 First up ANIMAL STUDIES 2015: Acute and long term effects of brief Sevoflurane anesthesia during the early postnatal period in rats 30 minute exposure rapidly induced developmental stagedependent, region specific, transient changes in dendritic spine densities These findings did not persist when examined 3 months post exposure Short and long term memory were NOT significantly affected Qiu L, et al. Acute and longterm effects of brief sevoflurane anesthesia during the early postnatal period in rats. Toxicol Sci. 2015 Sep 30. pii: kfv219. [Epub ahead of print] 23 2015: Neonatal mice exposed to titrated sevoflurane for 6 hours Increased apoptosis Impaired long term memory NO autism like behavior NO change in general activity of anxiety These results conflict with prior data during similar testing where sevoflurane exposure was constant and autism like behavior was demonstrated Chung W, et al. Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors. Paediatric Anesthesia. Oct;25(10):1033-45. 21 2015: Potential adverse effects of prolonged Sevoflurane exposure on developing monkey brains Neonatal monkeys were exposed to 2.5% Sevoflurane for 9 hours Elevated cytokine levels in exposed brains; extensive neural damage found in frontal cortex Most classes of lipids were reduced in Sevoflurane exposed brains Liu F, et al. Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage. Toxicol Sci. 2015 Oct;147(2):562-72 24 4
2015: Potential adverse effects of multiple anesthetic exposures on neonatal monkeys emotional reactivity to acute stressors Neonatal Rhesus monkeys were exposed to 2.5% Sevoflurane for 4 hours or brief maternal separations on PND 6 10 and again 2 4 weeks later Monkeys were tested at 6 months of age Increased anxiety related behaviors in exposed v. controls Early Exposure and Learning Disabilities Population: Birth Cohort from Olmsted County Minnesota 593 children with exposure <4 years born 1976 1982 Outcome measures: Learning Disability and/or ADHD Findings: No differences with one exposure, but 2 or more were more likely to have abnormal outcome Limitations: Pulse ox and capnography not standard of care; Halothane and NO used; External validity and high migration rates Raper J, et al. Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthes. 2015 Nov;123(5):1084-92. 25 Wilder RT, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110:796-804. Flick RP, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128:e1053-61. 28 Is Precedex the Answer? Dexmedetomidine attenuates neurotoxicity induced by prenatal propofol exposure Precedex is a selective alpha 2 adrenoreceptor agonist with antiapoptotic properties in several brain injury models Precedex prevented neurocognitive deficit in fetal rats administered propofol AND precedex v. propofol alone in utero Cognitive and Behavioral Outcomes Population: Birth Cohort from Olmsted County Minnesota 350 children with exposure <2 years born 1976 1982 matched to 2 unexposed control children Outcome measures: Learning Disability, Individualized Education program, and group administered tests of achievement and cognition Findings: No differences with one exposure, but 2 or more were more likely to have abnormal outcome Adjusted for health status Cases matched to controls including factors known to influence LD (gender, mom education, gestational age) Li J, et al. Dexmedetomidine Attenuates Neurotoxicity Induced by Prenatal Propofol Exposure. J Neurosurg Anesthesiol. 2015 Apr 2. Epub ahead of print. 26 Flick RP, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics, 2011:128(5)e1053-e1061) 29 Behavioral and Developmental Disorders Next up RETROSPECTIVE COHORT STUDIES Population: NYS Medicaid Dataset 383 children <3 years who underwent hernia repair with matched controls Outcome measures: Behavioral outcome code Findings: Adjusting for age, sex, race, confounding diagnoses at birth, hernia repair patients were more than twice as likely to have abnormal outcome Limitations: Unknown type, frequency and duration of anesthesia exposure DiMaggio C, et al. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21:286-91. 30 5
Cognitive Performance Population: Netherlands Twin Registry Outcome measures: Educational achievements at age 12 years or problems reported by teachers Findings: Exposure <3 years had reduced outcomes; no differences between discordant twins Limitations: Small n for discordant twins (15% of sample) but no findings in this subset Meta analyses 2012: Bayesian meta analysis of 12 eligible studies suggest modestly elevated risk of adverse behavioral or developmental outcomes in children who were exposed to anesthesia/surgery during early childhood 2014: SR and meta regression of 7 eligible studies suggest modestly elevated risk of adverse ND outcomes in children exposed <3 years, especially multiple 2015: Meta analysis of 13 eligible studies assessing neurodevelopmental damage from single GA before 3 years suggest modestly elevated risk of ND disorders Bartels M, et al. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12:246-53. 31 34 Language and Cognitive Function Population: Raine cohort from Western Australia Outcome measures: complex neuropsychiatric tests, standardized test (school) performance, ICD 9 codes Findings: Exposed children <3 years had deficits in language and abstract reasoning Where are we now ONGOING AND PROSPECTIVE STUDIES Limitations: All surgeries (including neurosurgeries); unknown duration and frequency of exposure Ing C, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476-85. 32 Academic Performance Population: Danish birth cohorts from 1986 1990 Outcome measures: Academic achievements in adolescence Findings: No difference after adjusting for known confounders (sex, birth weight, and maternal age and education) Limitations: Academic achievement does not test all neurodevelopmental domains Hansen TG, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114:1076-1085. 33 36 6
Pediatric Anesthesia and NeuroDevelopment Assessment 37 What about peds anesthesia? 87% provide information to faculty 97% provide information to residents and fellows Conferences>GR>JC>Informal Discussion>Reponses to Queries 90% DO NOT have consensus on how to modify anesthesia to minimize risk 91% discuss risk with parents ONLY IF asked 6% discuss as a routine part of preoperative evaluation Very few programs had formal method of discussion or parent handout Ward CG, et al. Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practice at US teaching institutions. Paediatr Anaesth. 2015 Nov. Epub ahead of print. 41 General Anesthesia compared to Spinal Why it s still a tough question to answer 39 Dimsa N, Hansen TG. Pediatric anesthesia and neurotoxicity: can findings be translated from animals to humans? Minerva Anestesiologica 2016 July;82(7):791-6. 7
Not All Tests Are Equal References Many different tests used in outcome studies matters Neuropsychiatric tests > ICD 9 codes > academic performance The age at testing matters Ing CH, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology. 2014;120:1319-32. 43 Bhattacharyya N. Ambulatory pediatric otolaryngologic procedures in the United States: characteristics and perioperative safety. Laryngoscope. 2010 Apr;120(4):821 5. Wang X, et al. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta regression. PLoS One. 2014 Jan 20;9(1):e85760. Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J. 2009 Jun;26(2):91 108 Rosenfeld RM, et al. Office Insertion of Tympanostomy Tubes without Anesthesia in Young Children. Otolaryngol Head Neck Surg. 2015 Oct 6. pii: 0194599815608366. [Epub ahead of print] Collaco JM, et al. Interdisciplinary pediatric aerodigestive care and reduction in health care costs and burden. JAMA Otolaryngol Head Neck Surg. 2015 Feb;141(2):101 5. Stratmann G, et al. Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long term neurocognitive function. Anesth Analg. 2010 Feb;11(2):431 7. Liu J, et al. Effects of Sevoflurane on Young Male Adult C57BL/6 Mice Spatial Cognition. PLoS One. 2015 Aug 18;10(8):e0134217. Chung W, et al. Sevoflurane exposure during the neonatal period induces long term memory impairment but not autism like behaviors. Paediatric Anesthesia. Oct;25(10):1033 45. Qiu L, et al. Acute and long term effects of brief sevoflurane anesthesia during the early postnatal period in rats. Toxicol Sci. 2015 Sep 30. pii: kfv219. [Epub ahead of print] Liu F, et al. Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage. Toxicol Sci. 2015 Oct;147(2):562 72. Raper J, et al. Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthes. 2015 Nov;123(5):1084 92. Li J, et al. Dexmedetomidine Attenuates Neurotoxicity Induced by Prenatal Propofol Exposure. J Neurosurg Anesthesiol. 2015 Apr 2. Epub ahead of print. Wilder RT, et al. Early exposure to anesthesia and learning disabilities in a population based birth cohort. Anesthesiology. 2009;110:796 804. Flick RP, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128:e1053 61. DiMaggio C, et al. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21:286 91. DiMaggio et al. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113:1143 51. Bartels M, et al. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12:246 53. Ing C, et al. Long term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476 85. Hansen TG, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114:1076 1085. DiMaggio C, et al. Pediatric Anesthesia and Neurodevelopmental Impairments: A Bayesian Meta Analysis. J Neurosurg Anesthesiol. 2012 Oct;24(4):376 381. http://smarttots.org/smarttots releases consensus statement regarding anesthesia safety in children/ http://smarttots.org/smarttots releases consensus statement regarding anesthesia safety in young children/ http://smarttots.org/general anesthesia causes no cognitive deficit in infants/ www.kidspandastudy.org https://clinicaltrials.gov/ct2/show/nct00756600 Ward CG, et al. Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practice at US teaching institutions. Paediatr Anaesth. 2015 Nov. Epub ahead of print. 46 Putting it all together Animal studies fairly consistently show evidence of neurotoxicity Cohort studies inconsistently show abnormal neurodevelopmental outcomes Take home points Consider necessity and frequency of interventions requiring GA Combine multiple procedures Consider conscious sedation or play therapy when possible Thank you! Growing Pedi ENT team Clinic availability 4 days per week OR 4 days per week How to reach us Page on call resident Daytime attending call schedule Clinic: (210) 358 0500 44 47 Future Directions what can we do? Survey study to assess and increase awareness Engage parents and anesthesiologists in discussions Await ongoing study results; participate in studies when possible Assess risk of radiation from CT v. risk of anesthsia for an MRI 45 8