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