Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia

Department of Anesthesiology, Columbia University College of Physicians and Surgeons, 622 W 168th St, BHN 4-440, New York, NY 10032, USA.
PEDIATRICS (Impact Factor: 5.47). 08/2012; 130(3):e476-85. DOI: 10.1542/peds.2011-3822
Source: PubMed


Over the past decade, the safety of anesthetic agents in children has been questioned after the discovery that immature animals exposed to anesthesia display apoptotic neurodegeneration and long-term cognitive deficiencies. We examined the association between exposure to anesthesia in children under age 3 and outcomes in language, cognitive function, motor skills, and behavior at age 10.
We performed an analysis of the Western Australian Pregnancy Cohort (Raine) Study, which includes 2868 children born from 1989 to 1992. Of 2608 children assessed, 321 were exposed to anesthesia before age 3, and 2287 were unexposed.
On average, exposed children had lower scores than their unexposed peers in receptive and expressive language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E]) and cognition (Colored Progressive Matrices [CPM]). After adjustment for demographic characteristics, exposure to anesthesia was associated with increased risk of disability in language (CELF-R: adjusted risk ratio [aRR], 1.87; 95% confidence interval [CI], 1.20-2.93, CELF-E: aRR, 1.72; 95% CI, 1.12-2.64), and cognition (CPM: aRR, 1.69; 95% CI, 1.13-2.53). An increased aRR for disability in language and cognition persisted even with a single exposure to anesthesia (CELF-R aRR, 2.41; 95% CI, 1.40-4.17, and CPM aRR, 1.73; 95% CI, 1.04-2.88).
Our results indicate that the association between anesthesia and neuropsychological outcome may be confined to specific domains. Children in our cohort exposed to anesthesia before age 3 had a higher relative risk of language and abstract reasoning deficits at age 10 than unexposed children.

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Available from: Guohua Li, May 13, 2014
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    • "Other aspects of PDA ligation that may contribute to the risk of NDI include the effects of anesthesia and postoperative hemodynamic compromise. Recent cohort studies, including sibling studies, have associated the administration of anesthesia in infancy and early childhood with NDI.[464748495051] This association was weakened after adjustment for key covariates, such as perinatal characteristics (e.g. "
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    ABSTRACT: Observational studies have associated patent ductus arteriosus (PDA) ligation in preterm infants with increased chronic lung disease (CLD), retinopathy of prematurity, and neurodevelopmental impairment at long-term follow-up. Although the biological rationale for this association is incompletely understood, there is an emerging secular trend toward a permissive approach to the PDA. However, insufficient adjustment for postnatal, pre-ligation confounders, such as intraventricular hemorrhage and the duration and intensity of mechanical ventilation, suggests the presence of residual bias due to confounding by indication, and obliges caution in interpreting the ligation-morbidity relationship. A period of conservative management after failure of medical PDA closure may be considered to reduce the number of infants treated with surgery. Increased mortality and CLD in infants with persistent symptomatic PDA suggests that surgical ligation remains an important treatment modality for preterm infants.
    04/2014; 3(2):67-75. DOI:10.4103/2249-4847.134670
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    • "The doses of sedatives or anesthetics used in our experiments are doses required for the degree of sedation that human premature infants experience when they are subjected to procedural sedation or surgical anesthesia, except that procedural sedation sometimes involves continuous or repeated exposure over a period of days or weeks, and in our study mice were exposed on only a single occasion. While extrapolation from rodents to humans is always fraught with uncertainties, the original evidence documenting apoptogenicity of sedative and anesthetic drugs [1,2,3,6] was generated in infant rodents, then was reproduced in infant and fetal non-human primates [28,29,30,31,32,33,34,35,37,38,39,40], and there now are seven recently published studies [53,54,55,56,57,58,59] documenting that brief exposure of human infants to anesthesia is associated with increased risk for long-term neurobehavioral disturbances, including disturbances relevant to both AD/HD and learning disability domains. While some of the studies [55,56,57] have been interpreted as evidence that it may require multiple exposures or a total exposure duration ≥2 h for a significant neurocognitive disability effect, other studies [53,54,58,59] support the interpretation that a single exposure to anesthesia for less than 2 h is sufficient to increase the risk for neurocognitive impairment. "
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    ABSTRACT: Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects.
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    ABSTRACT: A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice exert detrimental effects on the developing brain, notably enhanced neuroapoptosis. Some studies have also indicated that animals exposed to general anesthesia may experience long term neurobehavioral deficits later in life. The neurotoxic effects seem to be dose-dependent and have been suspected to occur at certain early developmental stages. Initially, the animal studies comprised primarily rodents but recently they have been confirmed in non-human primates. Recently, a number of (mainly retrospective) human cohort studies have been published with inconsistent results. While some studies have indicated an association between anesthesia and surgery and adverse neurobehavioral outcome, other studies have indicated no association. The cohort studies have many constraints and shortcomings. While prospective studies are underway, they will not provide any answers for several more years. The aim of this review is to provide the reader with a summary of recent human cohort studies and discuss their limitations and weaknesses. Although disturbing, the animal data lacks verification in humans. To date there are no data to support any change in clinical pediatric anesthetic practice. Any such change will be premature and potentially dangerous until we have evidence as to if and how general anesthesia impairs neurocognition and behaviour in infants and young children.
    09/2013; 3(3). DOI:10.1007/s40140-013-0019-4
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