A presentation by Pia Glatz at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine. All available content from SSAI2017: https://scanfoam.org/ssai2017/ Delivered in collaboration between scanFOAM, SSAI & SFAI.

1. Young Brains and Anesthesia:
How Big Are the Risks?
Pia Glatz
Kalmar

2. Conflicts of interest: None
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3.  Jevtovic-Todorovic et al 2003
 Rat pups anesthetized on postnatal day 7 with midazolam,
isoflurane, NO for 6 hours
 Excessive neuronal apoptosis
 Impaired memory, learning, behaviour
 Impaired cognitive function

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• Difficult to compare neonatal animals to neonates/infants
• Long duration of anesthesia exposure
• Fixed dosing, poor correlation animals/humans
• No control of airway, ventilation, circulation, fluids
• High mortality (20-80% according to investigators)
Critical issues in animal studies

5.  Raper et al 2015
 Coleman et al 2017
 Relevant anesthesia protocols
 Relevant duration
 Reliable monitoring
 Results: Multiple exposures result in long-term behavioral
consequences
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6. Human studies
 Retrospective cohort studies
 Mixed results, generally weak
evidence for an association
 Stronger association with multiple
exposures
 Adjustments attempt to reduce
impact of confounding
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7. Human studies
 Design
 Outcome measure – what?
 Outcome measure – when?
 Confounding
 Effect of anesthesia or surgery or other
condition?
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8.  O’Leary et al 2016
 28 366 exposed – 55 910 matched controls
 Born 1999 – 2007, 0–5 years at exposure
 Outcome measure: EDI (Early Development Index), lowest 10%
 All types of surgery, ENT and inguinal hernia repair most
common
 Exclusions: diagnoses of developmental disabilities, cancer
therapy, history of fetal intervention…
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9.  O’Leary et al 2016
 Results: Slightly higher risk for exposed (adjusted odds ratio
1.05)
 Subgroup analyses: No difference if exposed < age 2 years
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10.  Graham et al 2016
 3 850 exposed (single), 620 exposed (multiple) – 13 586
matched controls
 Born 2001-2006, 0-4 years at exposure
 Outcome measure: EDI (Early Development Index)
 All types of surgery, ENT and dental surgery most common
 Exclusions: Diagnosis of developmental disabilities
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11.  Graham et al 2016
 Results: Small but statistically significant difference
 Subgroup analyses: No difference if exposed < age 2 years
 No difference with multiple exposures
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12.  Sun et al 2016
 105 exposed compaired with 105 unexposed siblings
 Born 1997-2010, 0-3 years at exposure
 Outcome measure: IQ at age 8-15
 Inguinal hernia surgery
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13.  Sun et al 2016
 Results: No difference
 Age at exposure had no impact
 Subgroup analyses: No difference with longer duration (up to
120 min)
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14.  Davidson et al 2016
 Randomized to general or awake-regional anesthesia
 722 children randomized, data from 532
 Born 2006-2012, 0-5 months at exposure
 Outcome: IQ at age 5 => 2018
 Secondary outcome: Neurodevelopment assessed with Bayley-
III at age 2
 Inguinal hernia surgery
 Exclusions: existing risk factors for neurologic injury
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15.  Davidson et al 2016
 Results: No difference
 Results from IQ-test at age 5 in 2018…?
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16.  Glatz et al 2016
 33 514 exposed (single), 3 640 exposed (multiple) – 159 619
matched controls
 Born 1973-1993, 0–4 years at exposure
 Outcome measure: school grades at age 16, IQ test scores at
age 18 (boys)
 All types of surgery, ENT and inguinal hernia repair most
common
 Exclusions: diagnoses and surgery deemed to affect cognitive
development such as seroius malformation, cancer,
neurosurgery…
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17.  Glatz et al 2016
 Results: Small but statistically significant difference
 Subgroup analyses: No difference if exposed < age 3 years
 Increasing difference with multiple exposures
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18. Relative mean difference in grades Operated-Control (percent units)

19. Relative mean difference in grades Operated-Control (percent units)

20.  Glatz et al 2016
 Results: Small but statistically significant difference
 Subgroup analyses: No difference if exposed < age 3 years
 Increasing difference with multiple exposures
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21. Relative mean difference in grades Operated-Control (percent units)

22. Gender
Boys vs. Girls
Month of birth
Decembervs. January
Mothers education
10-12 years vs. >12 years
Inguinal hernia
Operated - Control
All operations
Operated - Control
Mean (95% CI)
-9.88 (-10.07, -9.68)
-5.34 (-5.80, -4.89)
-9.89 (-10.17, -9.61)
-0.35 (-0.85, 0.15)
-0.40 (-0.68, -0.11)
Impact of otherfactors known to
influence school marks (% change)

23. Conclusions
 There is preclinical evidence that anesthetic drugs affect brain
development
 How translate to humans?
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24. Conclusions
 For ethical reasons human studies are hard to design
 Later human studies have shown none or a small impact of
general anesthesia and surgery on cognitive development
 No evidence for increased vulnerability at the youngest age
intervals
 Causation cannot be established with cohort studies
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25. Conclusions
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”Cause for concern? Yes
Cause for continued research efforts? Definitely
Cause to adjust sound clinical practice? No. Stay tuned.”