Anaesthesia and Neurotoxicity
Andrew DavidsonAndrew Davidson
Royal Children’s Hospital Royal Children’s Hospital Melbourne AUSTRALIA Melbourne AUSTRALIA
http://www.smarttots.org
Rodent data up to 2010
• Neuronal apoptosis in rodent models– Ketamine, isoflurane, midazolam, propofol,
sevoflurane– Dose effect– Combination worse– Window of vulnerability day 7 in a rat– Some evidence for long term neurobehavioural
effect
Mechanism
• May be related to inactivity • May be related to changing ontogeny of
receptors• May be due to upregulation of NMDR receptor
• Ketamine in monkeys
• Apoptosis– 24 hours ketamine, 5 day old monkey
• No apoptosis – 3 hours ketamine, 5 day old monkey– 24 hours ketamine, 35 day old monkey
• Big doses• Need big doses in monkeys to have an effect
Slikker et al. Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey. Toxicological Sciences 2007; 98: 145-158
• Day 6 monkeys• 5hrs 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 2011
• Monkeys exposed to 24 hrs ketamine as day 5 infants
• Now 3½ years old: cognitive impairments– poorer performance in learning and colour and position
discrimination tasks – deficits in accuracy of task performance & response
speed– differences in motivation
• Day 15 rat pups• 5hrs anaesthesia: propofol,
ketamine, midazolam
• Increased dendritic spine density
Control KetaminePropofol
• Day 16 rat pups• Isoflurane,
desflurane, sevoflurane
• 30, 60, 120 minutes
• No cell death• Increased spine
density Control 120 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 apoptosis– “protective”
• Opioids– no evidence for apoptosis
Problems with animal studies
• Duration of exposure
• Dose of agent
• Monitoring
• Length of neurodevelopment
• Plasticity
• Effect of surgery
• Lumbar intrathecal morphine• Rats – P3, P10, P21
• Therapeutic dose • Toxicity• Therapeutic index
Therapeutic index
• Toxic dose/effective dose
• P3: >3/0.01 >300• P21: >3/0.15 >20
• Rats; P3, P7, P21• Ketamine; 3-10 mg/kg
• Effective dose• Toxicity• Therapeutic index
Therapeutic index
• Toxic dose/effective dose
• P3 3/3 1• P21 15/15 1
Human studies
2008 Mayo Clinic study
• 5357 children in a population based retrospective birth cohort – “Rochester epidemiology project”– Register of all children born 1976-82 in five
townships in Olmsted county Minnesota who stayed local for 5 years
• 593 surgery before age of 4 • Adjusted for gender, birth weight, gestational age
• 932 had learning disability
Unadjusted hazard ratios
Adjusted hazard ratios
Any 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)
Dose effect – increased risk of disability with duration and number of anaesthetics
• 383 children born in NY state cared for by Medicaid that had a hernia repair < 3yrs of age
• 5050 randomly selected controls matched on age• Adjusted for age, gender, race and presence of
complicating diagnoses at birth
• Behavioral or developmental disorder– 17 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 1986-1990• 2689 inguinal hernia repair• 14,575 Controls (5% of all children in Denmark)
• Outcome school test at 9th grade (age 15-16 years)
• Hernia group do worse• No 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 studies
• Little 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
• Confounding– Many known strong confounding factors– Probably many unknown confounding factors– Adjustments are not perfect & BIG doesn’t really help
Anaesthesia is associated with surgery
Surgery is associated with pathology
• Hormonal “Stress”• Inflammatory response• Circulatory instability• Respiratory compromise• Extra lines & handling• Temperature instability
Surgery poor outcome
• Genetic abnormality• Malformations• Prematurity• Sepsis
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
Good Bad
Reduces stressReduces painNeuro protection
ApoptosisDendritic development
Anaesthesia
Effects may be disproportionate in different situations
Summary
• Animal evidence – Strong for histological change – Some evidence for change in function
• Human evidence– Some evidence for an association between
surgery/anaesthesia and poor outcome– Role of anaesthesia very unclear
Recommendations
• “Avoid elective surgery in infants”• Don’t withhold analgesia and anaesthesia for
necessary surgery and procedures
• Is one drug better ? – Avoid prolonged use of high dose ketamine in
infants– Dexmedetomidine, opioids may be preferable
• Be very careful changing safe established practices due to theoretical risks
Future studies
• GAS study– RCT hernia GA versus RA
• Raine cohort – Western Australian birth cohort
• PANDA study – Hernia repair and matched
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