Anaesthesia and Neurotoxicity Andrew Davidson
Royal Childrens Hospital Melbourne AUSTRALIA
http://www.smarttots.org
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
Propofol
Which agents are good? Dexmedetomidine, xenon no apoptosisprotective
Opioidsno evidence for apoptosis
Problems with animal studiesDuration of exposure
Dose of agent
Monitoring
Length of neurodevelopment
Plasticity
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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