Anesthetic Neurotoxicity in Children: Review and Update?

Transcription

1 Anesthetic Neurotoxicity in Children: Review and Update? Randall Flick MD, MPH Associate Professor of Anesthesiology & Pediatrics Chair, Division of Pediatric Anesthesiology Medical Director, Mayo Eugenio Children s Hospital Mayo Clinic CHM circa 1935

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3 Place NEJM article here

4 The Problem? Millions of young children are exposed to anesthetic agents each year worldwide. Concerns have been raised as to the safety in young children of commonly used anesthetics & Nonanesthetic drugs. Apoptotic Neurodegenerative Injury

5 What Drugs are Involved? Implicated agents GABA agonists NMDA antagonists Anesthetics including Benzodiazepines propofol/barbiturates Nitrous oxide Volatile agents (All) Ketamine Etomidate

6 1999 First report that NMDA antagonists cause widespread apoptotic neurodegeneration in rodent brains Similar findings for GABA A agonists, ethanol, antiepileptics, midazolam, and a variety of anesthetics Multiple species The issue. Clinically relevant doses & durations Memory & Behavioral defects (water maze) Is this clinically significant in humans? Ikonomidou et al, Science 283:70, 1999

7 Children are Very Difficult to Study What is the next best thing? Ketamine 122 d gest, - 24 hr 5 d, 35 d- 3 hrs 5d, 35d - 24 hrs

8 In press 3/11

9 Is 24 hrs of exposure clinically relevant?

10 What is the equivalent human age to a 6 day old Monkey 6 d s ~ 6 mo

11 Is this clinically significant in humans? Kalkman et. al. Retrospective pilot study Urologic procedures Disturbed Neurodevelop. Validated parental checklist Disturbed behavior increased w/ decreased age O.R. were not significant N needed 2,268

12 Monozygotic dis/concordant twin study. 1,143 monozygotic twin pairs Parental report of anesthetic prior to age 3 & from 3-12 yrs. Educational achievement at 12. Standardized tests Teacher rating Exposure prior to three Reduced school performance Not different than unexposed co-twin

13 DiMaggio A Retrospective Cohort Study of the Association of Anesthesia and Hernia Repair Surgery With Behavioral and Developmental Disorders in Young Children Retrospective cohort analysis of children enrollees in the New York State Medicaid program. A birth cohort: DiMaggio, C. et al. J Neurosurg Anesth October 2009; 21: children, inguinal hernia repair during age 0-3 Control group 5,050 children with no history of hernia-repair before age 3 Adjusted for age, sex, and low birth weight Billing Codes c/w behavioral/learning problems Hernia repair children had over 2-fold higher frequency of developmental or behavioral disorder (adjusted hazard ratio 2.3)

14 Surgery a surrogate for anesthetic exposure No information on anesthetic No access to medical record Endpoints unclear ICD 9 codes (developmental delay)

15 Single anesthetic exposure Effect of hernia repair rather than anesthesia Misclassification; outpatient exposures into controls

16 Dimaggio/Davidson et. al. Australian pregnancy cohort 2868 kids born between Retrospective longitudinal study over 16 years f/u. Exposure(surgery)prior to 3 yrs Outcomes Comprehensive neurodevelopmental battery Multiple tests over time Dichotomous Results Abstract reasoning OR 3.4 Language impairment OR ~ 2 for expressive, receptive & total Access to medical record?, Surrogate exposure?, Follow-up rates, Number/duration of exposure C/W Mayo findings

17 Two Published Mayo Studies All using similar resources Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Sprung J, Flick RP, Wilder RT, Katusic SK, Pike TL, Dingli M, Gleich SJ, Schroeder DR, Barbaresi WJ, Hanson AC, Warner DO. And two more soon

18 Wilder Study All birth records, school records & medical records including all episodes of anesthesia/surgery, available for all kids. 593/5718 given general anesthesia prior to age 4 yrs Thus possible to determine if there is an association between exposure to anesthesia/surgery and the development of LD

19 Number of Anesthetic Exposures Dose Response? Hazard Ratio Adjusted* 95% C.I. P Number of exposures < (N=4765) reference 1 (N=448) to (N=101) to or more (N=44) to 4.24 *Adjusted for sex, birth weight (<2500, 2500) and gestational age (<32 weeks, 32 to <37 weeks, 37 weeks) Wilder et al, Anesthesiology 110:796, 2009

20 Total duration (continuous variable)* Hazard Ratio 95% C.I. P to Categorical (30 min) No anesthesia (N=4765) Duration of Anesthesia Dose Response? reference 30 minutes (N=95) to to 60 min (N=135) to to 90 min (N=134) to to 120 min (N=87) to min (N=142) to 2.19 *per 30 minutes Wilder et al, Anesthesiology 110:796, 2009

21 Diagnosis of LD in Children With and Without Exposure to Anesthesia Between Age % (95% C.I. 26.2% to 42.9%) 20.4% (95% C.I. 16.3% to 24.3%) 20.0% (95% C.I. 18.8% to 21.3%) LD determined by one of 3 formulas Wilder et al, Anesthesiology 110:796, 2009

22 What about exposure to anesthesia during Cesarean Delivery? Learning disability (%) CD, GENERAL 19.4% (95% CI 13.2% to 25%) VAGINAL DELIVERY 20.8% (95% CI 19.5% to 22.0%) CD, REGIONAL 15.4% (95% CI 11.0% to 19.7%) Age (years) Cumulative percentage of any LD

23 Weaknesses Is anesthesia/surgery simply a marker for children at risk of LD? Co-morbidities cause LD and contribute to the need for surgery/anesthesia (e.g., hearing deficits in children requiring myringotomies) Higher burden of illness may affect learning (e.g., absenteeism from school) More chances for LD to be to detected by physicians (selection bias) Old Cohort Outdated anesthetic Lack of monitoring (pulse oximetry, capnography)

24 Next step. SmartTots (FDA) Control for Co-Morbidity Matched set design, same cohort Anesthesia prior to age 2 years (Wilder age 4 yrs) 2:1 Match (700 unexposed/350 exposed) Endpoints LD group test data IEP services Co-morbidity adjusters (determined at age 4-5 yrs) ASA PS Hopkins ACG (Adjusted Clinical Groups)

25 Preliminary Results. Adjusted for matching variables only 37% (C.I ) 24% (C.I. 18 to 29%) 21% (C.I. 18 to 24% Similar results obtained with morbidity adjustment via Hopkins ACG System and ASA PS

26 Speech/Language IEP Services (Individualized Education Plan) 22% (C.I. 10 to 31%) 7% (C.I. 4 to 10%) 6% ( C.I. 4 to 8%

27 Emotional Behavioral Disorder (EBD) IEP Services (Individualized Education Plan) 5% (C.I. 4-7%) 4% (C.I. 2-6%) 0% (0 0%)

28 What do we know? Single anesthetics do not seem to have an effect. Repeated anesthetic exposures consistently show an effect. Effect persists despite adjustment for comorbidity. Learning (reasoning), speech and language but not behavior appear to be affected.

29 Bob Wilder Robert Colligan Mike Olson Beka Katusic Amy Weaver Thanks Randall Flick Juraj Sprung Bill Barbaresi Darrell Schroeder Bob Voigt Andy Hanson

30 So What do we tell the parents? Associations are not necessarily causal!!!! Brief single anesthetic exposures do not seem to cause problems. Beware of unintended consequences We need more information before we change practice

31 Thanks!

32 Is there anything that isn t a problem in young children?

33 What about the Connection to ADHD? Attention Deficit Hyperactivity Disorder Among Children with 0, 1 or Multiple Exposures to Anesthesia (Preliminary Data) Unadjusted

34 Is there a Connection to Autism? Behavioral Effects in animal models Neonatal Exposure to Sevoflurane Induces Abnormal Social Behaviors & Deficits in Fear Conditioning in Mice Satomoto et al 6 d. o. mice 3% Sevoflurane 6 h Behavioral outcomes Emotional responses Fear/anxiety responses Spatial/olfactory memory Fear conditioning Social recognition/interaction Results Deficits in fear conditioning Abnormal social interaction

35 Hazard Ratios Number of exposures to anesthesia A different measure of abnormal behavior Autism Hazard Ratio Unadjusted 95% C.I. P Haza rd Ratio Adjusted* 95% C.I. P referent referent to to or more to to 3.78 Duration of anesthetic exposure (m) referent referent 1 to to to or more to to 4.30 *Adjusted for gestational age, birth weight and mother s age.

36 ALSDAC No direct communication from the FDA to the public Professional societies should communicate to their members. Parents should be informed on an individual basis that accounts for Drug Duration Indication Co-morbidity

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38 What about the Connection to Autism? Unadjusted analysis Control (N=230) Autism (N=115) P-value Number of exposures to anesthesia (80% ) 85 (74% ) (14% ) 19 (17% ). 2 or more 15 (7% ) 11 (10% ) Duration of anesthetic exposure (m) (80% ) 85 (74% ). 1 to (12% ) 12 (10% ). 76 or more 20 (9% ) 18 (16% )

39 Learning Disabilities Birth Cohort All children born in Rochester, MN who remained in Rochester after age 5 (N=5,718) Learning Disability (LD) primary endpoint Records reviewed for potential LD from: All public + private schools + home schools All medical providers Reading Center/Dyslexia Institute of Minnesota Individually administered IQ and achievement tests used to diagnose LD (reading, written language, math) prior to age 19

40 Isoflurane produces greater injury with less exposure

41 Co-morbidity? Distribution of ASA Physical Status Wilder et. al. Wilder et al, Anesthesiology 110:796, 2009

42 Recent Developments Isoflurane Neurotoxicity Is Mediated by p75ntr-rhoa Activation and Actin Depolymerization. Lemkuil, Brian; Head, Brian; Pearn, Matthew; Patel, Hemal; Drummond, John; Patel, Piyush Anesthesiology. 114(1):49-57, January 2011.

43 Sprung et. al. What about exposure to anesthesia during Cesarean Delivery? Of the birth cohort, 497 delivered via CD 193 general anesthesia 304 regional anesthesia Analysis repeated using mode of delivery as a covariate Other covariates included gestational age, sex, birth weight, maternal education, and number of anesthesia exposures prior to age 4