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Anaesthesia and Neurotoxicity Andrew Davidson Royal Children’s Hospital 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 Slikker et al. Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey. Toxicological Sciences 2007; 98: 145-158 • 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 • 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 Propofol Ketamine • Day 16 rat pups • Isoflurane, desflurane, sevoflurane • 30, 60, 120 minutes • No cell death • Increased spine density Control 30 min 60 min 120 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: • P21: >3/0.01 >3/0.15 >300 >20 • Rats; P3, P7, P21 • Ketamine; 3-10 mg/kg • Effective dose • Toxicity • Therapeutic index Therapeutic index • Toxic dose/effective dose • P3 • P21 3/3 15/15 1 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 J Neurosurg Anesth • 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) • 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 Research and Human Genetics 2009 • 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 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 Surgery poor outcome • • • • • • Hormonal “Stress” Inflammatory response Circulatory instability Respiratory compromise Extra lines & handling Temperature instability Pathology poor outcome • • • • Genetic abnormality Malformations Prematurity Sepsis 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 Anaesthesia Good Reduces stress Reduces pain Neuro protection Bad Apoptosis Dendritic development 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