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Anaesthesia and Neurotoxicity. Andrew Davidson Royal Children’s Hospital Melbourne AUSTRALIA. Rodent data up to 2010. Neuronal apoptosis in rodent models Ketamine, isoflurane, midazolam, propofol, sevoflurane Dose effect Combination worse - PowerPoint PPT Presentation

Text of Anaesthesia and Neurotoxicity

  • Anaesthesia and Neurotoxicity Andrew Davidson

    Royal Childrens Hospital Melbourne AUSTRALIA


  • Rodent data up to 2010Neuronal apoptosis in rodent modelsKetamine, isoflurane, midazolam, propofol, sevofluraneDose effectCombination worseWindow of vulnerability day 7 in a ratSome evidence for long term neurobehavioural effect

  • MechanismMay be related to inactivity May be related to changing ontogeny of receptorsMay be due to upregulation of NMDR receptor

  • Ketamine in monkeys

    Apoptosis24 hours ketamine, 5 day old monkey

    No apoptosis 3 hours ketamine, 5 day old monkey24 hours ketamine, 35 day old monkey

    Big dosesNeed big doses in monkeys to have an effectSlikker et al. Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey. Toxicological Sciences 2007; 98: 145-158

  • Day 6 monkeys5hrs isoflurane 0.7-1.5%

    Increased apoptosis

  • Paule et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011Monkeys exposed to 24 hrs ketamine as day 5 infants

    Now 3 years old: cognitive impairmentspoorer performance in learning and colour and position discrimination tasks deficits in accuracy of task performance & response speeddifferences in motivation

  • Day 15 rat pups5hrs anaesthesia: propofol, ketamine, midazolam

    Increased dendritic spine density

  • Day 16 rat pupsIsoflurane, desflurane, sevoflurane30, 60, 120 minutes

    No cell deathIncreased spine density

    Control120 min60 min30 min

  • Which agents are bad? Isoflurane, desflurane, sevoflurane

  • Which agents are bad? Isoflurane, desflurane, sevoflurane

    Midazolam, diazepam, clonazepam

    Phenobarbital, pentobarbital

    Chloral hydrate


  • Which agents are good? Dexmedetomidine, xenon no apoptosisprotective

    Opioidsno evidence for apoptosis

  • Problems with animal studiesDuration of exposure

    Dose of agent


    Length of neurodevelopment


    Effect of surgery

  • Lumbar intrathecal morphineRats P3, P10, P21

    Therapeutic dose ToxicityTherapeutic index

  • Therapeutic indexToxic dose/effective dose

    P3: >3/0.01>300P21: >3/0.15 >20

  • Rats; P3, P7, P21Ketamine; 3-10 mg/kg

    Effective doseToxicityTherapeutic index

  • Therapeutic indexToxic dose/effective dose

    P3 3/31P2115/151

  • Human studies

  • 2008 Mayo Clinic study5357 children in a population based retrospective birth cohort Rochester epidemiology projectRegister of all children born 1976-82 in five townships in Olmsted county Minnesota who stayed local for 5 years593 surgery before age of 4 Adjusted for gender, birth weight, gestational age

    932 had learning disability

  • Dose effect increased risk of disability with duration and number of anaesthetics

    Unadjusted hazard ratiosAdjusted hazard ratiosAny anaesthetic (593) 1.27 (1.05- 1.53)1.20 (0.99-1.46)

    1 (449)1.05 (0.84- 1.32)1.00 (0.79- 1.27)

    2 (100)1.78 (1.22- 2.59)1.59 (1.06- 2.37)

    3 or more (44)2.50 (1.55- 4.04)2.60 (1.60- 4.24)

  • 383 children born in NY state cared for by Medicaid that had a hernia repair < 3yrs of age 5050 randomly selected controls matched on ageAdjusted for age, gender, race and presence of complicating diagnoses at birth

    Behavioral or developmental disorder17 in hernia group (4.4%) 59 in non-hernia group (1.2%)

    Adjusted Hazard Ratio 2.3 (1.3 - 4.1)

    J Neurosurg Anesth

  • Danish birth cohort 1986-19902689 inguinal hernia repair14,575 Controls (5% of all children in Denmark)

    Outcome school test at 9th grade (age 15-16 years)

    Hernia group do worseNo evidence for an association when adjusted for confounding factors

  • Twin study: monozygotic concordant-discordant design 1143 monozygotic twin pairs born 1986-95

    Any anaesthesia Prior to 3 Prior to 12

    Educational achievement at age 12

    Twin Research and Human Genetics 2009

  • Problems with human studiesLittle idea which age is most at risk & many studies have older children

    No idea how long an exposure is bad

    Bias is difficult to eradicate in cohort studies that compare to population norms

    Little idea which outcome to look at & many studies have multiple outcomes and very course outcomes

    ConfoundingMany known strong confounding factorsProbably many unknown confounding factorsAdjustments are not perfect & BIG doesnt really help

  • Anaesthesia is associated with surgery

    Surgery is associated with pathology

  • Hormonal StressInflammatory responseCirculatory instabilityRespiratory compromiseExtra lines & handlingTemperature instabilitySurgery poor outcome

  • Genetic abnormalityMalformationsPrematuritySepsis Pathology poor outcome

  • Surgery or anaesthesia?Not able to disentangle effect of surgery and anaesthesia

    Surgery may be the harm

    Anaesthesia may have benefits to reduce surgical harm

  • GoodBadReduces stressReduces painNeuro protectionApoptosisDendritic developmentAnaesthesiaEffects may be disproportionate in different situations

  • Summary Animal evidence Strong for histological change Some evidence for change in function

    Human evidenceSome evidence for an association between surgery/anaesthesia and poor outcomeRole of anaesthesia very unclear

  • Recommendations Avoid elective surgery in infantsDont withhold analgesia and anaesthesia for necessary surgery and procedures

    Is one drug better ? Avoid prolonged use of high dose ketamine in infantsDexmedetomidine, opioids may be preferable

    Be very careful changing safe established practices due to theoretical risks

  • Future studiesGAS studyRCT hernia GA versus RARaine cohort Western Australian birth cohortPANDA study Hernia repair and matched

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