Anesthetic-Induced Neuronal Brain Injury in Infants: Finding an Answer with Clinical Studies

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Anesthetic-Induced Neuronal Brain Injury in Infants: Finding an Answer with Clinical Studies Andrew Davidson Royal Children s Hospital Melbourne AUSTRALIA Local anesthesia infiltration by the surgeon

Attempts have been made to reduce this struggling by giving the child a sugar nipple soaked in whisky to suck. It is only moderately efficient.

1 Anesthetic-Induced Neuronal Brain Injury in Infants: Finding an Answer with Clinical Studies Andrew Davidson Royal Children s Hospital Melbourne AUSTRALIA Local anesthesia infiltration by the surgeon has fairly wide popularity. However this method of anesthesia is not completely satisfactory, since the child cries and struggles. Attempts have been made to reduce this struggling by giving the child a sugar nipple soaked in whisky to suck. It is only moderately efficient. In the first place the whisky itself supplied by the hospital is usually of poor quality but fortunately the child never gets enough of it to cause any real harm. Digby Leigh 1949 Local anesthesia infiltration by the surgeon has fairly wide popularity. However this method of anesthesia is not completely satisfactory, since the child cries and struggles. Attempts have been made to reduce this struggling by giving the child a sugar nipple soaked in whisky to suck. It is only moderately efficient. In the first place the whisky itself supplied by the hospital is usually of poor quality but fortunately the child never gets enough of it to cause any real harm. Local anesthesia infiltration by the surgeon has fairly wide popularity. However this method of anesthesia is not completely satisfactory, since the child cries and struggles. Attempts have been made to reduce this struggling by giving the child a sugar nipple soaked in whisky to suck. It is only moderately efficient. In the first place the whisky itself supplied by the hospital is usually of poor quality but fortunately the child never gets enough of it to cause any real harm. Digby Leigh 1949 Digby Leigh 1949 Local anesthesia infiltration by the surgeon has fairly wide popularity. However this method of anesthesia is not completely satisfactory, since the child cries and struggles. Attempts have been made to reduce this struggling by giving the child a sugar nipple soaked in whisky to suck. It is only moderately efficient. In the first place the whisky itself supplied by the hospital is usually of poor quality but fortunately the child never gets enough of it to cause any real harm. Emergence of the question Laboratory research on mechanisms of foetal ethanol toxicity GABA agonists & NMDA antagonists cause neuronal apoptosis in laboratory rats Neonatologists suspect poor neuro developmental outcomes with surgery What factors contribute to poor outcome Digby Leigh

2 Extrapolating animal data to humans Comparing period of vulnerability uncertain Comparing dose uncertain Damage in humans may be less as exposure is short relative to total period of normal apoptosis in humans Human development is longer May be more scope for recovery, or May make us more vulnerable Lab work difficult to incorporate any neuro protective effects of anaesthesia in face of pain and inflammation Human studies Does anaesthesia exposure result in poor neurodevelopmental outcome? Elements of the question P - population E - exposure C - comparator O - outcome T - timeframe Issues in study design Bias Confounding Major surgery Congenital diaphragmatic hernia Oesophageal atresia Congenital heart disease Some evidence for higher risk of worse neurobehavioral outcome Loepke & Soriano. Anesthesia & Analgesia June 2008 Boston circulatory arrest cohort Children with isolated congenital malformations born abdo wall defect 12 CDH 27 small intestinal 13 Oesopahgeal atresia WISC-III year 8 year Normal Outcome at age 24 months Psychomotor 88.0 ( ) Mental development ( ) J Ped Surg full-scale verbal perform ance W echsler Preschool and Primary Scale of Intelligence 2

3 Single centre post arterial switch surgery 8 years Best friend buddy age matched control IQ Control Cardiac surgery is associated with surgery is associated with pathology J Thor Car Surg 2004: 127; poor outcome Pathology poor outcome Hormonal Stress Inflammatory response Circulatory instability Respiratory compromise Extra lines & handling Temperature instability Genetic abnormality Malformations Prematurity Sepsis Pathology Pathology Outcome Outcome 3

4 Adjust with regression Pathology Outcome Cohort from 1983, full term infants 30 major surgery 13 medical ICU 29 healthy matched control infants J Ped Surg 2001: 36; Outcome - school performance aged 11 years English Mathematics Science Overall teacher rating No difference between medical ICU and control Multivariate regression - risk for worse outcome (for all measures) A randomised trial of indomethacin prophylaxis in infants <1000 g at birth 426 infants with symptomatic PDA 110 surgery 316 medical therapy Neurological impairment in survivors 53% Medical therapy 34% Multivariate regression: OR 1.98, P=0.009 J Pediatr : Sensorineural disability 221 extremely premature babies Born 1985 Outcome: IQ at 5 yrs of age IQ 89 (IQR 82-98) No surgery 98 (IQR ) Non-surgical (n=165) No disability Mildmoderate disability 72% 25% 3% Severe disability All surgical (n=53) 49% 38% 13% Multivariate regression - risk of moderate or severe disability : Odds Ratio 11.4 (95% CI: ) J Paed Child Health 1996: 32; Inguinal hernia (n=16) 44% 37% 19% 4

5 2008 Mayo Clinic study Population based retrospective birth cohort Rochester epidemiology project Register of all children born in five townships in Olmsted county Minnesota who stayed local for 5 years Exposure before age 4 years Outcome Learning disability Adjustment Gender, birth weight, gestational age 5357 included 932 had learning disability 593 surgery before age of 4 Those who had surgery Lower gestational age Lower birth weight Male Higher maternal education Unadjusted hazard Adjusted hazard ratios ratios Any anaesthetic (593) 1.27 ( ) 1.20 ( ) 1 (449) 1.05 ( ) 1.00 ( ) 2 (100) 1.78 ( ) 1.59 ( ) 3 or more (44) 2.50 ( ) 2.60 ( ) Dose effect increased risk of disability with duration and number of anaesthetics J Neurosurg Anesth Population All children born in NY state cared for by Medicaid & linked to Medicaid utilisation records up to 2002 Exposed Those that had a hernia repair < 3yrs of age Comparison Randomly selected matched on age Outcome time in days to diagnosis of: Subsequent code for unspecified delay or behavioural disorder, Mental retardation, Speech or learning problem, Autism Adjustment Age, gender, race and presence of complicating diagnoses at birth 112,851 birth records Children with hernia repair: 383 Comparison group: 5050 Hernia group more likely to be: Black Male Have a complicating diagnosis i at birth Behavioral or developmental disorder 17 in hernia group (4.4%) 59 in non-hernia group (1.2%) Adjusted Hazard Ratio 2.3 ( ) Population based retrospective birth cohort Rochester epidemiology project Exposure General anaesthesia for cesarean delivery Comparison Local anaesthesia for cesarean delivery & Vaginal delivery Outcome Learning disability Adjusted for Gestational age, sex, birth weight, maternal education, number of anaesthesia exposures before age 4 5

5320 children 193 Cesarean under GA 304 Cesarean under regional Those with cesarean under GA had: Lower weight Lower gestational age More pregnancy complications More emergencies 921 with learning

6 5320 children 193 Cesarean under GA 304 Cesarean under regional Those with cesarean under GA had: Lower weight Lower gestational age More pregnancy complications More emergencies 921 with learning disability 20.8% Vaginal delivery 19.4% Cesarean under GA 15.4% Cesarean under regional When adjusted Hazard ratio 064( ( ) comparing caesarean under regional to vaginal?? No difference GA and RA? Cohort Infants born < 33 weeks gestation Exposure > 7 days opioids and/or sedatives Outcome Moderate or severe disability at age 5 years Adjustment Propensity score, gestational age Arch Pediatr Adolesc Med surviving infants with data 1497 had data for propensity scores 113 exposed Follow-up data available for 86% Disability 42.3% exposed 25.7% unexposed Risk ratio for disability Unadjusted 1.6 (1.3 to 2.1) Adjusted 1.0 ( ) Twin study: monozygotic concordant-discordant design Dutch twin register 1143 monozygotic twin pairs born Exposure: any anaesthesia Prior to 3 Prior to 12 Outcome: Educational achievement at age 12 Twin Research and Human Genetics

7 No surgery Twins concordant for exposure 2 0 Twins discordant for exposure 1 1 Twins concordant for non exposure 0 2 Does anaesthesia exposure result in poor neurodevelopmental outcome? Elements of the question P - population E - exposure C - comparator O - outcome T - timeframe Issues in study design Bias Confounding P - population Little idea which age is most at risk & many studies have older children E - exposure No idea how long is bad? C - comparator Bias is difficult to eradicate in cohort studies O - outcome Little idea which outcome to look at & many studies have multiple outcomes and very course outcomes T - timeframe Don t know when the injury is apparent or if recovery possible or anaesthesia? Not able to disentangle effect of surgery and anaesthesia may be the harm may have benefits to reduce surgical harm Confounding Many known strong confounding factors Probably many unknown confounding factors Adjustments are not perfect & the more you make the weaker the power 7

8 Summary so far Good Bad Human data surgery may be associated with poor neurobehavioural outcome, but unknown if general anaesthetics contribute to injury o reduce injury Reduces stress Reduces pain Neuro protection Apoptosis Dendritic development Effects may be disproportionate in different situations Future cohort studies Useful outcomes form cohort studies Mayo cohort study with matched controls Huge Danish population study matching surgery in infancy with school outcome PANDA study cohort study 500 children aged 6-11 who had hernia surgery aged < 3yrs with sibling controls RAINE study Existing West Australian birth cohort with extensive neurobehavioural data; anaesthesia aged < 1yr with matched controls Might demonstrate surgery/anaesthesia is not associated with poor neurobehavioural outcome in some groups Identify at risk groups for poor outcome Age Concurrent pathologies Identify domains of neurobehavioral outcome where outcome is poor Age at which they can be assessed Surrogate outcomes Trials Trials regional vs general anaesthesia No confounding No confounding No No No No No No No No What dose What age Which outcome What dose What age Which outcome 8

9 Questions for a trial of GA vs RA Does general anaesthesia produce clinically relevant neurotoxicity? Can I give either GA or RA and not worry about the neurobehavioral outcome Which anaesthetic has best outcome? Does general anaesthesia produce clinically relevant neurotoxicity? Equivalence trial Problems Dose/ Age/ Outcome Regional placebo, regional may be damaging or protective But, unlikely that RA is damaging to cortex Possible RA may be protective - reduce stress related injury better than GA: increase the appearance of GA looking toxic Possible GA is neuro protective in some circumstances : may make any direct toxicity less obvious Can I give either GA or RA and not worry about the neurobehavioral outcome? Equivalence trial Problems Dose/ Age/ Outcome Which anaesthetic has best outcome? Superiority trial GA versus Regional Opioid versus GA etc Problems Dose/ Age/ Outcome Ethics GAS G - general anaesthesia A - apoptosis - apnoea S - spinal anaesthesia A multi-site RCT comparing regional and general anaesthesia on neurodevelopmental outcome and apnoea in neonates GAS Equivalence trial 660 neonates for inguinal hernia repair Australia, USA, Canada, Italy, UK, The Netherlands Funding: NH&MRC, FDA, HTA, CIHR Randomised Randomised Spinal or Sevoflurane GA Outcome 2 yrs & 5 yrs Answers in 2014 &

A large investigator driven multinational trial in paediatric anaesthesia involving neonates 700 600 500 GAS recruitment graph as at 1 January 2010 Target Challenges Ethics & regulatory hurdles

Jul-11 Jan-12 Summary Some evidence that infants who have major surgery may have poor neurobehavioural outcome Many issues with confounding Role of any anaesthetic neurotoxicity unclear Better

10 A large investigator driven multinational trial in paediatric anaesthesia involving neonates GAS recruitment graph as at 1 January 2010 Target Challenges Ethics & regulatory hurdles Funding Culture Co-operation & Co-ordination Pa articipants Actual Feasibility failed spinals follow-up 0 Month Jan-07 Jul-07 Jan-08 Jul-08 Jan-09 Jul-09 Jan-10 Jul-10 Jan-11 Jul-11 Jan-12 Summary Some evidence that infants who have major surgery may have poor neurobehavioural outcome Many issues with confounding Role of any anaesthetic neurotoxicity unclear Better matched cohort studies need to be (are being) done to define at risk groups and relevant outcomes More clinical trials need to be (can be) done to optimise the anaesthetic and perioperative care in neonates 10

Anesthetic Neurotoxicity in Children: Review and Update?

Anesthetic Neurotoxicity in Children: Review and Update? Randall Flick MD, MPH Associate Professor of Anesthesiology & Pediatrics Chair, Division of Pediatric Anesthesiology Medical Director, Mayo Eugenio