The uncomfortable reality … We simply do not know if general anesthesia negatively impacts the neurocognitive development of our small children

doi:10.1016/j.ijporl.2015.05.011

International Journal of Pediatric Otorhinolaryngology

Volume 79, Issue 9, September 2015, Pages 1379-1381

https://doi.org/10.1016/j.ijporl.2015.05.011 Get rights and content

Abstract

Annually in the United States more than one million children under the age of 5 years are exposed to anesthetics for therapeutic and diagnostic procedures. Pre-clinical data in animal models has consistently shown that anesthetic exposure to the developing brain results in long-term cognitive deficits. Current clinical data addressing the safety of these pharmaceutical agents on the developing human brain is limited. Recently, there has been an enormous amount of attention directed at this potential public health issue in both pre-clinical investigations and ongoing human research. A number of these studies should add to our understanding about the impact anesthetic exposure will have on the developing human brain. Until then, there is little data that absolutely reassures clinicians and parents that the pharmaceutical agents used are indeed safe for our children.

The uncomfortable reality is that despite the fact that there are more than one million children younger than 5 years old who receive general anesthesia in the United States annually, and thousands more who are deeply sedated for imaging and diagnostic studies or as a necessary adjunct to care in the intensive care unit, there is little data that assures clinicians and parents that the pharmaceutical agents used are indeed safe for the developing brain. That said, there are no convincing human data to suggest that they are not.

References (16)

M.G. Paule et al.
Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys
Neurotoxicol. Teratol.
(2011)
B. Clancy et al.
Extrapolating brain development from experimental species to humans
Neurotoxicology
(2007)
M.E. McCann et al.
Clinical research approaches to studying pediatric anesthetic neurotoxicity
Neurotoxicology
(2009)
B.M. Psaty et al.
Neurotoxicity of generic anesthesia agents in infants and children: an orphan research question in search of a sponsor
J. Am. Med. Assoc.
(2015)
B.A. Rappaport et al.
Anesthetic neurotoxicity – clinical implications of animal models
N. Eng. J. Med.
(2015)
Pediatric anesthesia big advances for our smallest patients
ASA Newsletter
(2015)
M. Perouansky et al.
Neurotoxicity of general anesthetics: cause for concern?
Anesthesiology
(2009)
V. Jevtovic-Todorovic et al.
Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits
J. Neurosci.
(2003)

There are more references available in the full text version of this article.

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2018, International Journal of Developmental Neuroscience
Citation Excerpt :
These children are more likely than others to have structural and functional impairments of the brain (Scott et al., 2011; Ashkenazi et al., 2013; Feldman et al., 2012; Travis et al., 2015; Martin et al., 2015). We reasoned that if very preterm children who had systemic inflammation during the first postnatal month are more likely than others to have structural and/or functional abnormalities of the brain (Mann and Kahana, 2015; Hartkopf et al., 2017; Korzeniewski et al., 2015; O'Shea et al., 2014), and children who have structural and/or functional abnormalities of the brain are more likely than others to have learning limitations (Scott et al., 2011; Ashkenazi et al., 2013; Feldman et al., 2012; Travis et al., 2015; Martin et al., 2015), then children who had systemic inflammation during the first postnatal month might be at increased risk of learning problems. The “paucity of protectors” hypothesis offers one explanation for why extremely preterm newborns are at increased risk of limitations of brain development, and of brain damage.
Difficulties with reading and math occur more commonly among children born extremely preterm than among children born at term. Reasons for this are unclear.
We measured the concentrations of 27 inflammatory-related and neurotrophic/angiogenic proteins (angio-neurotrophic proteins) in multiple blood specimens collected a week apart during the first postnatal month from 660 children born before the 28th week of gestation who at age 10 years had an IQ ≥ 70 and a Wechsler Individual Achievement Test 3rd edition (WIAT-III) assessment. We identified four groups of children, those who had a Z-score ≤ −1 on the Word Reading assessment only, on the Numerical Operations assessment only, on both of these assessments, and on neither, which served as the referent group. We then modeled the risk of each learning limitation associated with a top quartile concentration of each protein, and with high and lower concentrations of multiple proteins.
The protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio-neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-α in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins.
High concentrations of angio-neurotrophic proteins appear to reduce/moderate the risk of each learning limitation associated with systemic inflammation. The three categories of limitations have protein profiles with some similarities, and yet some differences, too.
Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage
2018, European Journal of Paediatric Neurology
Citation Excerpt :
Other strengths include efforts to minimize observer variability in the assessment of ultrasound scans,27 and protein data of high quality,119 and high content validity.29,120–122 Our findings continue to support the inference that systemic inflammation, especially if sustained, is a correlate (either cause or consequence) of brain damage.123 What is new is our documentation that high concentrations of selected neurotrophic factors are indeed associated with some diminution of the brain damage associated with high concentrations of inflammation-related proteins.
To assess to what extent the blood concentrations of proteins with neurotrophic and angiogenic properties measured during the first postnatal month convey information about the risk of sonographically-identified brain damage among very preterm newborns.
Study participants were 1219 children who had a cranial ultrasound scan during their stay in the intensive care nursery and blood specimens collected on 2 separate days at least a week apart during the first postnatal month. Concentrations of selected proteins in blood spots were measured with electrochemiluminescence or with a multiplex immunobead assay and the risks of cranial ultrasound images associated with top-quartile concentrations were assessed.
High concentrations of multiple inflammation-related proteins during the first 2 postnatal weeks were associated with increased risk of ventriculomegaly, while high concentrations of just 3 inflammation-related proteins were associated with increased risk of an echolucent/hypoechoic lesion (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high concentrations of IL6R and bFGF appeared to modulate the increased risks of ventriculomegaly and an echolucent lesion associated with inflammation. More commonly high concentrations of putative protectors/repair-enhancers did not appear to diminish these increased risks.
Our findings provide support for the hypothesis that endogenous proteins are capable of either protecting the brain against damage and/or enhancing repair of damage.
Antecedents of Screening Positive for Attention Deficit Hyperactivity Disorder in Ten-Year-Old Children Born Extremely Preterm
2018, Pediatric Neurology
The incidence of attention deficit hyperactivity disorder is higher among children born very preterm than among children who are mature at birth.
We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4, which allowed classification of the child as having or not having symptoms of attention deficit hyperactivity disorder. For 422 children, we also had a teacher report, and for 583 children, we also had a parent report of whether or not a physician made an attention deficit hyperactivity disorder diagnosis.
The risk profile of screening positive for attention deficit hyperactivity disorder based on a parent's report differed from the risk profile based on the teacher's report, whereas the risk profile according to a physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age (parent, physician, and two observers), maternal obesity (parent, physician, and two observers), maternal smoking (parent, physician, and two observers), magnesium given at delivery for seizure prophylaxis (parent and two observers), recovery of Mycoplasma sp. from the placenta (teacher and two observers), low gestational age (parent and two observers), low birth weight (teacher and physician), singleton (parent, physician, and two observers), male (parent, teacher, physician, and two observers), mechanical ventilation on postnatal day seven (physician), receipt of a sedative (parent and two observers), retinopathy of prematurity (parent), necrotizing enterocolitis (physician), antibiotic receipt (physician and two observers), and ventriculomegaly on brain scan (parent and two observers).
The multiplicity of risk factors identified can be subsumed as components of four broad themes: low socioeconomic state, immaturity or vulnerability, inflammation, and epigenetic phenomena.
Decreasing intraoperative delays with meaningful use of the surgical safety checklist
2018, Surgery (United States)
Purposeful completion (fidelity) more than simple adherence to items in the surgical safety checklist may improve operating room efficiency and patient safety. The purpose of this study was to evaluate intraoperative delays and correlate them with adherence and fidelity to the preincision surgical safety checklist.
Trained observers evaluated surgical safety checklist compliance during 3 observation periods from 2014–2016. Degree of adherence, checkpoint verbalization, fidelity, and meaningful completion were assessed. Delays were categorized as missing or malfunctioning equipment, staff error, and medication issues. Descriptive statistics, analysis of variance, logistic regression, χ² and Student t test were used to analyze results.
Of the 591 cases observed, 19% (n = 110) had at least one documented, intraoperative delay. The majority of delays were related to missing (50%) or malfunctioning (30%) equipment. Compared with cases without delays, cases with delays did not have a different mean degree of adherence (96.3 ± 7.6% vs 95.6 ± 5.8%, P = .36). Degree of fidelity was different between cases with and without delays (mean fidelity 77.1 ± 14.9% vs 80.5 ± 7.14.2%, P = .03).
The preincision SSC is a communication tool offering an opportunity to discuss potential concerns and anticipated intraoperative needs. Fidelity rather than adherence to the surgical safety checklist seems to diminish intraoperative delays.
Developmental neurotoxicity of general anesthetics
2018, Handbook of Developmental Neurotoxicology
Many studies using laboratory animals have demonstrated that exposure to general anesthesia during critical periods of development can be harmful to the immature brain. In particular, preclinical studies have shown that developmental exposure to general anesthetics results in widespread neuronal cell death, as well as long-term deficits in cognitive function. Nevertheless, the ability of general anesthetics to produce similar effects in humans has not been proven. Although many retrospective observational studies in humans have shown an association between developmental exposure to anesthesia and adverse neurobehavioral outcomes, other studies have not. To clarify this relationship, continuing clinical investigations are underway. Likewise, preclinical studies are continuing to explore the potential mechanisms of action responsible for anesthetic-induced neurotoxicity, as well as to identify effective prevention and treatment strategies. This research aims to shed further light upon the phenomenon, allowing for the development of ameliorative or preventative strategies leading to best practice guidance for the protection of public health.
More than 3 hours and less than 3 years old. Safety of anesthetic procedures in children under 3 years of age, subject to surgeries of more than 3 hours
2017, Revista Espanola de Anestesiologia y Reanimacion

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Review ArticleThe uncomfortable reality … We simply do not know if general anesthesia negatively impacts the neurocognitive development of our small children

Abstract

Neurotoxicol. Teratol.

Neurotoxicology

Neurotoxicology

Neurotoxicity of generic anesthesia agents in infants and children: an orphan research question in search of a sponsor

J. Am. Med. Assoc.

Anesthetic neurotoxicity – clinical implications of animal models

N. Eng. J. Med.

Pediatric anesthesia big advances for our smallest patients

ASA Newsletter

Neurotoxicity of general anesthetics: cause for concern?

Anesthesiology

Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits

J. Neurosci.

Review Article
The uncomfortable reality … We simply do not know if general anesthesia negatively impacts the neurocognitive development of our small children