Anaesthesia and Neurotoxicity Andrew Davidson Andrew Davidson Royal Children’s Hospital Royal Children’s Hospital Melbourne AUSTRALIA Melbourne AUSTRALIA
Jan 12, 2016
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