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Use of anesthetics in young children Consensus statement of the European Society of Anaesthesiology (ESA), the European Society for Paediatric Anaesthesiology (ESPA), the European Association of Cardiothoracic Anaesthesiology (EACTA), and the European Saf

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Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
EDITORIAL
Use of anaesthetics in young children
Consensus statement of the European Society of
Anaesthesiology, the European Society for Paediatric
Anaesthesiology, the European Association of Cardiothoracic
Anaesthesiology and the European Safe Tots Anaesthesia
Research Initiative
Tom G. Hansen
European Journal of Anaesthesiology 2017, 34:327–328
Jointly published in Pediatric Anesthesia 2017, 27:558–559
Experimental studies have shown that general anaes-
thetics may cause a variety of morphological changes
in the developing immature brain of laboratory animals.
1
In addition, there is some evidence that long-term and
prolonged exposure may be worse than short-term
exposure in some animal species.
2,3
However, the
relevance of these findings in human beings is currently
unknown,
4,5
and studies have shown controversial
results.
6–8
Although a number of investigations in
humans have demonstrated an association between sur-
gical and anaesthetic exposure and negative neurodeve-
lopmental outcome,
9–11
several others have been unable
to find such an association or only in a minor subset of
exposed children with or without extensive individual
neurocognitive testing.
12– 18
It remains, therefore, very
difficult to identify whether any negative neurodevelop-
mental effects are because of the anaesthetic drugs, the
conduct of anaesthesia, surgical trauma or the underlying
clinical conditions.
3–19
Importantly, however, two prospective human studies,
with the most robust designs, indicate that short-term
single exposure of 60 min or less to surgery and anaes-
thesia is not associated with measurable long-term neuro-
developmental problems.
12,16
Food and Drug Administration statement
On the 14th of December 2016, the Food and Drug
Administration (FDA) issued a warning statement for
the United States of America regarding the use of anaes-
thesia or sedation in young children (and pregnant
women).
20
This statement highlights potential risk of
anaesthetic procedures that last longer than 3 h or
multiple procedures required in children less than 3 years
of age. The evidence to support such warning is currently
insufficient and incomplete. Therefore, this FDA
warning is not shared by the European Societies listed
below.
The European Society of Anaesthesiology/
European Society for Paediatric
Anaesthesiology/European Association of
Cardiothoracic Anaesthesiology/European
Safe Tots Anaesthesia Research Initiative
consensus statement
No child or pregnant woman should ever undergo any
medical procedure that is not necessary. Similarly, young
children (and pregnant women) should not undergo
surgery and general anaesthesia for trivial reasons. How-
ever, delaying or avoiding surgery may result in a signifi-
cant and real risk of a variety of adverse outcomes. If an
invasive procedure is necessary, adequate anaesthesia/
analgesia are mandatory. Indeed, there is good evidence
that inadequate anaesthesia and analgesia may result in
significant and serious complications.
21,22
There is cur-
rently no evidence to support the suggestion that a
change from established techniques for prolonged or
repeated procedures would have any impact on long-
term outcomes including neurocognition and develop-
ment in young children.
Eur J Anaesthesiol 2017; 34:327328
From the Department of Clinical Research – Anaesthesiology, University of Southern Denmark, Odense, Denmark
Correspondence to Tom G. Hansen, MD, co-Chair of European Safe Tots Anaesthesia Research Initiative, Department of Clinical Research Anaesthesiology,
University of Southern Denmark, Odense, Denmark
E-mail: tomghansen@dadlnet.dk
0265-0215 Copyright ß2017 European Society of Anaesthesiology. All rights reserved. DOI:10.1097/EJA.0000000000000629
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Furthermore, the implied ‘safe’ cut-off points of age
3 years or duration of procedure of 3 h quoted in the
FDA warning statement are not currently supported by
evidence derived from human studies.
Given the uncertainty in this domain, it is reasonable to
discuss all aspects of perioperative safety with patients,
parents and families. However, discussion of hypothetical
risks based primarily on animal research not confirmed in
human studies may create anxiety.
Established well tolerated anaesthetic techniques
delivered by trained and experienced staff in a paediatric
environment supported by the necessary clinical organ-
isation are essential factors for the delivery of well
tolerated anaesthesia and sedation in children.
23
Conclusion
There is currently no compelling evidence to change
anaesthetic practice, but anaesthesiologists should pro-
vide adequate information on the risks of avoiding a
necessary intervention/anaesthesia procedure as well as
on the potential risks associated with anaesthetic pro-
cedures. The European Societies listed above participate
in international collaborations and support the principles
of well tolerated conduct of anaesthesia in children and
pregnant women. Information for parents and infor-
mation for anaesthetists will be updated as and when
new issues arise.
Acknowledgements relating to this article
Assistance with the Editorial: none.
Financial support and sponsorship: none.
Conflict of interest: none.
Comment from the Editor: this Editorial was checked and accepted
by the editors but was not sent for external peer review. TGH is an
Associate Editor of the European Journal of Anaesthesiology.
References
1 Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common
anesthetic agents causes widespread neurodegeneration in the
developing rat brain and persistent learning deficits. J Neurosci 2003;
23:876– 882.
2 Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain:
mechanisms and relevance. Nat Rev Neurosci 2016; 18:705–717.
3 Zou X, Patterson TA, Divine RL, et al. Prolonged exposure to ketamine
increases neurodegeneration in the developing monkey brain. Int J Dev
Neurosci 2009; 27:727– 731.
4 Todd MM. Anesthetic neurotoxicity: the collision between laboratory
neuroscience and clinical medicine. Anesthesiology 2004; 101:227 –230.
5 Andropoulos DB, Greene MF. Anesthesia and developing brains
implications of the FDA warning. N Engl J Med 2017; 376:905 –907.
6 Hansen TG. Anesthesia-related neurotoxicity and the developing animal
brain is not a significant problem in children. Paediatr Anaesth 2015;
25:65– 72.
7 Rappaport BA, Suresh S, Hertz S, et al. Anesthetic neurotoxicity – clinical
implications of animal models. N Engl J Med 2015; 372:796 –797.
8 Psaty BM, Platt R, Altman RB. Neurotoxicity of generic anesthesia agents in
infants and children: an orphan research question in search of a sponsor.
JAMA 2015; 313:1515– 1516.
9 Ing C, DiMaggio C, Whitehouse A, et al. Long -term differences in language
and cognitive function after childhood exposure to anesthesia. Pediatrics
2012; 130:e476– e485.
10 Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and
learning disabilities in a population-based birth cohort. Anesthesiology
2009; 110:796– 804.
11 Ing CH, DiMaggio CJ, Malacova E, et al. Comparative analysis of outcome
measures used in examining neurodevelopmental effects of early childhood
anesthesia exposure. Anesthesiology 2014; 120:1319–3214.
12 Sun LS, Li G, Miller TL, et al. Association between a single general
anesthesia exposure before age 36 months and neurocognitive outcomes
in later childhood. JAMA 2016; 315:2312– 2320.
13 Hansen TG, Pedersen JK, Henneberg SW, et al. Academic performance in
adolescence after inguinal hernia repair in infancy: a nation-wide cohort
study. Anesthesiology 2011; 114:1076–1085.
14 Hansen TG, Pedersen JK, Henneberg SW, et al. Educational outcome in
adolescence following pyloric stenosis repair before 3 months of age: a
nation-wide cohort study. Paediatr Anaesth 2013; 23:883 –890.
15 Glatz P, Sandin RH, Pedersen NL, et al. Academic performance after
anesthesia and surgery during childhood a large scale nation-wide study.
JAMA Pediatr 2017; 171:e163470.
16 Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcome at
2 years of age after general anaesthesia and awake-regional anaesthesia in
infancy (GAS): an international multicentre, randomised controlled trial.
Lancet 2016; 387:239– 250.
17 O’Leary JD, Janus M, Duku E, et al. A population-based study evaluating the
association between surgery in early life and child development at primary
school entry. Anesthesiology 2016; 125:272–279.
18 Graham MR, Brownell M, Chateau DG, et al. Neurodevelopmental
assessment in kindergarten in children exposed to general anesthesia
before the age of 4 years. A retrospective study. Anesthesiology 2016;
125:667– 677.
19 Weiss M, Hansen TG, Engelhardt T. Ensuring safe anaesthesia for
neonates, infants and young children: what really matters. Arch Dis Child
2016; 101:650– 652.
20 FDA Drug Safety Communication. 2016 www.fda.gov/Drugs/DrugSafety/
ucm532356.htm.
21 Anand KJS, Hickey PR. Halothane-morphine compared with high dose
sufentanil for anesthesia and postop analgesia in neonatal cardiac surgery.
N Engl J Med 1992; 326:1– 9.
22 Anand KJS. Revisiting a dilemma: repetitive pain vs. opioid exposure? Acta
Paediatr 2016; 105:736– 737.
23 Weiss M, Vutskits L, Hansen TG, et al. Safe anesthesia for every Tot – the
SAFETOTS initiative. Curr Opin Anaesthesiol 2015; 28:302 –376.
328 Hansen
Eur J Anaesthesiol 2017; 34:327328
... До недавнего времени применение различных методов анестезии для детей считалось безопасным, однако многочисленные экспериментальные и клинические исследования показывают, что некоторые рутинно применяемые анестетики в педиатрической практике не настолько безвредны, как принято считать, и могут вызвать различные неблагоприятные последствия [24]. Управление по санитарному надзору за качеством пищевых продуктов и медикаментов США (FDA, Food and Drug Administration) выпустило предупреждение о потенциальных рисках повторного или длительного воздействия анестезии на младенцев, детей и беременных женщин [25]. Однако предупреждение FDA было поставлено под сомнение многими редакционными статьями и медицинскими сообществами из-за недостаточных и неубедительных клинических данных. ...
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Background: Animal studies demonstrate general anesthetic (GA) toxicity in the developing brain. Clinical reports raise concern, but the risk of GA exposure to neurodevelopment in children remains uncertain. Methods: The authors undertook a retrospective matched cohort study comparing children less than 4 yr of age exposed to GA to those with no GA exposure. The authors used the Early Development Instrument (EDI), a 104-component questionnaire, encompassing five developmental domains, completed in kindergarten as the outcome measure. Mixed-effect logistic regression models generated EDI estimates for single versus multiple GA exposure and compared both single and multiple exposures by the age of 0 to 2 or 2 to 4 yr. Known sociodemographic and physical confounders were incorporated as covariates in the models. Results: A total of 18,056 children were studied: 3,850 exposed to a single GA and 620 exposed to two or more GA, who were matched to 13,586 nonexposed children. In children less than 2 yr of age, there was no independent association between single or multiple GA exposure and EDI results. Paradoxically, single exposure between 2 and 4 yr of age was associated with deficits, most significant for communication/general knowledge (estimate, -0.7; 95% CI, -0.93 to -0.47; P < 0.0001) and language/cognition (estimate, -0.34; 95% CI, -0.52 to -0.16; P < 0.0001) domains. Multiple GA exposure at the age of 2 to 4 yr did not confer greater risk than single GA exposure. Conclusions: These findings refute the assumption that the earlier the GA exposure in children, the greater the likelihood of long-term neurocognitive risk. The authors cannot confirm an association between multiple GA exposure and increased risk of neurocognitive impairment, increasing the probability of confounding to explain the results.
Article
Importance Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. Objective To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. Design, Setting, and Participants Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. Exposures A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. Main Outcomes and Measures The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. Results Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = −0.2 (95% CI, −2.6 to 2.9); performance = 0.5 (95% CI, −2.7 to 3.7); and verbal = −0.5 (95% CI, −3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. Conclusions and Relevance 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. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.