The FDA has issued a warning regarding use of general anesthetic and sedation drugs in children under 3 years of age and in pregnant women in their third trimester — a warning that will change ...practice and raise questions that currently have no clear answers.
For more than 15 years, the potential for lasting neurotoxic effects of agents used to induce general anesthesia and sedation when administered to young children — and indirectly through pregnant women to fetuses with developing brains — has been a subject of concern and considerable research interest. The topic has been the focus of three public hearings by the Food and Drug Administration (FDA) since 2007, including an FDA Science Board meeting in November 2014, to better inform the public and practitioners about this potential problem and to foster a discussion between parents and physicians about potential risks posed by . . .
Over the past 20 years, hundreds of preclinical studies of the developing central nervous system have been published concluding that the common γ-aminobutryic acid and N-methyl-d-aspartate binding ...anesthetic agents cause neuroapoptosis and other forms of neurodegeneration. Some clinical studies, including controlled trials, both prospective and ambidirectional in design, indicate an association between any exposure (single or multiple) to anesthesia and surgery at a young age, generally less than 3–4 years, and later behavioral and neurodevelopmental problems. A consideration of neuroprotective strategies is important, as scientists and clinicians alike ponder methods to potentially improve the neurodevelopmental outcomes of the millions of infants and children who undergo surgery and anesthesia annually around the world. This review will address plausible neuroprotective strategies and include alternative anesthetics, neuroprotective nonanesthetic drugs, and physiologic neuroprotection.
As the field pediatric anesthesia advances and expands, so too does the gamut of challenges that are faced by today's anesthesiologists. Gregory's Pediatric Anesthesia aims to fully prepare trainees ...and experienced professionals for modern practice by equipping them with the knowledge and cutting-edge techniques necessary to safely and successfully anesthetize children for a range of different surgeries and other procedures. Supporting their work with current data and evidence, the authors explore topics including basic principles, potential complications, and best practice, and illustrate their findings with detailed case studies that cover all major subspecialties. This essential new edition includes access to illustrative videos and features new and expanded sections, such as: * Anesthesia for Spinal Surgery complications including postoperative blindness * Robotic surgery for Pediatric Urological Procedures * Anesthesia for Non-Cardiac Surgery in Patients with Congenital Heart Disease (new chapter) * Extensive additional ultrasound images for regional anesthesia * Neonatal Resuscitation * The Pediatric Surgical Home and Enhanced Recovery after Surgery (new chapter) Now in its sixth edition, Gregory's Pediatric Anesthesia continues to provide reliable and easy-to-follow guidance to all anesthesiologists caring for younger patients.
Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD).
We analyzed individual participant data from studies of children evaluated ...with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI).
Among 1770 subjects from 22 institutions, assessed at age 14.5 ± 3.7 months, PDIs and MDIs (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means (each P < .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P ≤ .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02).
Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources.
Background New intraparenchymal brain injury on magnetic resonance imaging is observed in 36% to 73% of neonates after cardiac surgery with cardiopulmonary bypass. Brain immaturity in this population ...is common. We performed brain magnetic resonance imaging before and after neonatal cardiac surgery, using a high-flow cardiopulmonary bypass protocol, hypothesizing that brain injury on magnetic resonance imaging would be associated with brain immaturity. Methods Cardiopulmonary bypass protocol included 150 mL · kg−1 · min−1 flows, pH stat management, hematocrit > 30%, and high-flow antegrade cerebral perfusion. Regional brain oxygen saturation was monitored, with a treatment protocol for regional brain oxygen saturation < 50%. Brain magnetic resonance imaging, consisting of T1-, T2-, and diffusion-weighted imaging, and magnetic resonance spectroscopy were performed preoperatively, 7 days postoperatively, and at age 3 to 6 months. Results Twenty-four of 67 patients (36%) had new postoperative white matter injury, infarction, or hemorrhage, and 16% had new white matter injury. Associations with preoperative brain injury included low brain maturity score ( P = .002). Postoperative white matter injury was associated with single-ventricle diagnosis ( P = .02), preoperative white matter injury ( P < .001), and low brain maturity score ( P = .05). Low brain maturity score was also associated with more severe postoperative brain injury ( P = .01). Forty-five patients had a third scan, with a 27% incidence of new minor lesions, but 58% of previous lesions had partially or completely resolved. Conclusions We observed a significant incidence of both pre- and postoperative magnetic resonance imaging abnormality and an association with brain immaturity. Many lesions resolved in the first 6 months after surgery. Timing of delivery and surgery with bypass could affect the risk of brain injury.
Background Expectations for outcomes after the neonatal arterial switch operation (ASO) continue to change. This cohort study describes neurodevelopmental outcomes at age 12 months after neonatal ...ASO, and analyzes both modifiable and nonmodifiable factors for association with adverse outcomes. Methods Patients who underwent an ASO (n = 30) were enrolled in a prospective outcome study, with comprehensive clinical data collection during the first 12 months of life. Brain magnetic resonance imaging was done preoperatively and 7 days postoperatively, and the Bayley Scales of Infant Development III was performed at age 12 months. Results Ten of 30 patients (33%) had preoperative magnetic resonance imaging injury; 13 of 30 patients (43%) had new postoperative magnetic resonance imaging injury. Twenty patients (67%) had Bayley Scales of Infant Development III: Cognitive Composite standard score mean was 104.8 ± 15.0, Language Composite standard score median was 90.0 (25th to 75th percentile, 83 to 94), and Motor Composite standard score mean was 92.3 ± 14.2. Best subsets multivariable analysis found associations between lower preoperative and intraoperative cerebral oxygen saturation, preoperative magnetic resonance imaging brain injury, total bypass time, and total midazolam dose and lower Bayley Scales of Infant Development III scores at age 12 months. Conclusions At 12 months after ASO, neurodevelopmental outcome means were within normal population ranges. The new associations reported in this study between potentially modifiable perioperative factors and outcomes require investigations in larger patient cohorts. Beyond survival, which was 100% in this cohort, factors influencing quality of life including neurodevelopmental outcomes should be routinely investigated in studies of ASO patients.
Summary
Background
Adverse neurodevelopmental outcomes are observed in up to 50% of infants after complex cardiac surgery. We sought to determine the association of perioperative anesthetic exposure ...with neurodevelopmental outcomes at age 12 months in neonates undergoing complex cardiac surgery and to determine the effect of brain injury determined by magnetic resonance imaging (MRI).
Methods
Retrospective cohort study of neonates undergoing complex cardiac surgery who had preoperative and 7‐day postoperative brain MRI and 12‐month neurodevelopmental testing with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley‐III). Doses of volatile anesthetics (VAA), benzodiazepines, and opioids were determined during the first 12 months of life.
Results
From a database of 97 infants, 59 met inclusion criteria. Mean ± sd composite standard scores were as follows: cognitive = 102.1 ± 13.3, language = 87.8 ± 12.5, and motor = 89.6 ± 14.1. After forward stepwise multivariable analysis, new postoperative MRI injury (P = 0.039) and higher VAA exposure (P = 0.028) were associated with lower cognitive scores. ICU length of stay (independent of brain injury) was associated with lower performance on all categories of the Bayley‐III (P < 0.02).
Conclusions
After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12 months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes.
Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be ...seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.
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