Pediatric Anesthetic Neurotoxicity An Update Phil G Morgan, MD University of Washington

Disclosures Sadly, none

What do we tell parents?

Developmental Neurotoxicity Animal Studies (How we got worried) Rodents Primates Others Clinical Studies (Does it actually matter?) Retrospective Prospective Obstetric Studies Mechanisms/Therapies 2015, what we tell parents FDA gets involved

Anesthesia --- 1981 the safest time from womb to tomb!

Nitrous oxide, versed, isoflurane (oxygen) Posterior cingulate cortex Jevtovic-Todorovic, J Neurosci (2003) Posterior cingulate cortex Subiculum

Nitrous oxide, versed, isoflurane (oxygen) Thalamus Jevtovic-Todorovic, J Neurosci (2003)

Jevtovic-Todorovic, J Neurosci (2003)

Exposed Exposed Unexposed Unexposed Jevtovic-Todorovic, J Neurosci (2003)

Fold Increase Apoptosis Post Natal Day Yon et al., Neurosci, 2005

Post Natal Day Fold Increase Apoptosis Yon et al., Neurosci, 2005

Apoptosis, Thalamus Anesthetic No Anesthetic Yon et al, Neurosci (2005)

Yon et al, Neurosci (2005)

Guinea Pigs in utero Rizzi et al, Brain Pathol (2008)

Caspase-3 Staining Rizzi et al, Brain Pathol (2008)

Neuronal Density Rizzi et al, Brain Pathol (2008)

What about primates?

Rhesus macaques were studied at a fetal age of G120 (corresponds in brain age to a late third-trimester human fetus), or at a neonatal age of P6 (corresponds to brain age of a 4–6-month-old human infant). Ansgar Brambrink

Fetal, EGA 120; PN6: 5 hours, propofol Creeley et al., BJA 2013, 110, 29.

Creeley et al., BJA 2013, 110, 29. Brambrink et al., Anesth 2010, 112, 834

Primates (multiple exposures) Rhesus monkeys 3 4-h exposures Scored @ 5 months N=8/9 Raper J, et al. Anesth 2015

Nice, but what about humans

2009

2009

2009 1153 monozygotic twins, single exposure before age 3 years Time of exposure not available Standardized achievement tests

2008

2011 Twins DiMaggio et al., A&A, 2011

All Studies Lin EP et al, 2017

All Studies Lin EP et al, 2017

Enter the GAS study And the T-Rex study And the Mask study And the UCSF study And the PANDA study

GAS Study

Davidson, Lancet, 2016

GAS Study Davidson, Lancet, 2016

Davidson, Lancet, 2016

GAS Study Strong evidence that exposure of just under an hour to a sevoflurane GA in infancy does not increase the risk of adverse neurodevelopmental outcome at two years of age. This is the strongest clinical evidence to date that just under an hour of sevoflurane GA in infancy does not result in significant neurotoxicity. Davidson, 2016

MASK Study Mayo Clinic combination of retrospective and prospective studies. Preliminary findings indicate that similar to their prior published study, multiple anesthetic exposures, but not a single exposure, are associated with an increased frequency of learning disability and attention deficit hyperactivity disorder.

UCSF Study 28 infants (<1 year of age) exposed to volatile anesthetic for longer than 2 hours exhibited a deficit in recognition memory compared with matched controls assessed between the ages of 6 and 11 years

PANDA Study The PANDA study was an ambidirectional, sibling-matched cohort study examining neurodevelopmental outcomes at ages 8 to 15 years in ASA 1 or 2 patients who had inguinal hernia surgery before the age of 3 against an unexposed sibling. A bias toward higher socioeconomic status among test participant families. Mostly males; average length of anesthetic exposure was 84 minutes.

PANDA Study Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood.

Anesthetic Neurotoxicity Fetal

Guinea Pigs in utero Rizzi et al, Brain Pathol (2008)

CUMC Study Maternal exposure Pregnant women between the ages of 18 and 45 with normal pregnancies between 2005 and 2010. Infants exposed to maternal regional anesthesia had greater brain volumes in bilateral frontal and right occipital lobes than infants who had no maternal exposure.

Mechanisms?

Wu J et al., Anesth 2016. 124, 624

Na et al., Neurotox Teratol 2017

Conclusions I Multiple mechanisms proposed May be possible to mitigate the effects

What do we tell parents? 2015 Discuss with parents and other caretakers the risks and benefits of procedures requiring anesthetics or sedatives, as well as the known health risks of not treating certain conditions. Recognize that current anesthetics and sedatives are necessary for infants and children who require surgery or other painful and stressful procedures

So, What do we tell parents? A survey by the Pediatric Anesthesiology Leadership Consortium and Directors 2015

http://www.pedsanesthesia.org

http://www.pedsanesthesia.org

http://www.pedsanesthesia.org

http://www.pedsanesthesia.org

http://www.pedsanesthesia.org

http://www.pedsanesthesia.org

FDA 12/14/2016 The FDA is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

So, What do we tell parents? Health care professionals should balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risks, especially for procedures that may last longer than 3 hours or if multiple procedures are required in children under 3 years. Discuss with parents, caregivers, and pregnant women the benefits, risks, and appropriate timing of surgery or procedures requiring anesthetic and sedation drugs.

Conclusions II Some anesthetics are neurotoxic in animals but exposure must be significant Effect is developmentally restricted and time dependent There is strongly suggestive data supporting some neurotoxicity in humans with multiple (or prolonged) exposures Should not avoid necessary procedures

Thank you