Anesthetics and sedatives: Toxic or protective for the developing brain?
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave, Cincinnati, OH 45229-3039, USA. Pharmacological Research
(Impact Factor: 4.41).
03/2012; 65(3):271-4. DOI: 10.1016/j.phrs.2011.10.001
Despite our insufficient understanding of the exact molecular mechanisms of general anesthetics and sedatives, every year millions of children are treated with these drugs in a seemingly safe manner. However, increasing evidence particularly from animal studies has suggested the possibility for deleterious effects in pediatric patients. All currently clinically utilized anesthetic drugs have been found to induce neuronal cell death in the developing brain and to potentially cause long-term neurological impairment. Conversely, painful stimuli without analgesia and anesthesia have also been shown to initiate a harmful stress response in young children and to trigger neurotoxic effects in the developing brain, which can be blunted by anesthetics. Moreover, anesthetic drugs may also confer neurological protection during hypoxic and ischemic insults. The mechanisms and human applicability of anesthetic neurotoxicity and neuroprotection remain under intense investigation and this Perspectives article summarizes the current state of research.
Available from: T. Kerner
- "The currently available experimental and clinical data addressing the toxic effects of anesthetics and sedatives and the impact of pain and stress on the developing brain are not sufficient and evidence-based enough to make any scientifically based recommendations for pediatric surgery or anesthesia , . Despite all limitations, the effects of anesthesia and the stress response and/or inflammatory response of surgery on the patients well-being cannot be dimissed. "
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ABSTRACT: Propofol is commonly used as sedative in newborns and children. Recent experimental studies led to contradictory results, revealing neurodegenerative or neuroprotective properties of propofol on the developing brain. We investigated neurodevelopmental short- and long-term effects of neonatal propofol treatment.
6-day-old Wistar rats (P6), randomised in two groups, received repeated intraperitoneal injections (0, 90, 180 min) of 30 mg/kg propofol or normal saline and sacrificed 6, 12 and 24 hrs following the first injection. Cortical and thalamic areas were analysed by Western blot and quantitative real-time PCR (qRT-PCR) for expression of apoptotic and neurotrophin-dependent signalling pathways. Long-term effects were assessed by Open-field and Novel-Object-Recognition at P30 and P120.
Western blot analyses revealed a transient increase of activated caspase-3 in cortical, and a reduction of active mitogen-activated protein kinases (ERK1/2, AKT) in cortical and thalamic areas. qRT-PCR analyses showed a down-regulation of neurotrophic factors (BDNF, NGF, NT-3) in cortical and thalamic regions. Minor impairment in locomotive activity was observed in propofol treated adolescent animals at P30. Memory or anxiety were not impaired at any time point.
Exposing the neonatal rat brain to propofol induces acute neurotrophic imbalance and neuroapoptosis in a region- and time-specific manner and minor behavioural changes in adolescent animals.
Available from: sciencedirect.com
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General anesthetics can induce apoptotic neurodegeneration and subsequent maladaptive behaviors in animals. Retrospective human studies suggest associations between early anesthetic exposure and subsequent adverse neurodevelopmental outcomes. The relevance of animal data to clinical practice is unclear and to our knowledge the causality underlying observed associations in humans is unknown. We reviewed newly postulated neurodevelopmental risks of pediatric anesthesia and discuss implications for the surgical care of children.
Materials and methods:
We queried the MEDLINE®/PubMed® and EMBASE® databases for citations in English on pediatric anesthetic neurotoxicity with the focus on references from the last decade.
Animal studies in rodents and primates demonstrate apoptotic neuropathology and subsequent maladaptive behaviors after exposure to all currently available general anesthetics with the possible exception of α2-adrenergic agonists. Similar adverse pathological and clinical effects occur after untreated pain. Anesthetic neurotoxicity in animals develops only after exposure above threshold doses and durations during a critical neurodevelopmental window of maximal synaptogenesis in the absence of concomitant painful stimuli. Anesthetic exposure outside this window or below threshold doses and durations shows no apparent neurotoxicity, while exposure in the context of concomitant painful stimuli is neuroprotective. Retrospective human studies suggest associations between early anesthetic exposure and subsequent adverse neurodevelopmental outcomes, particularly after multiple exposures. The causality underlying the associations is unknown. Ongoing investigations may clarify the risks associated with current practice.
Surgical care of all patients mandates appropriate anesthesia. Neurotoxic doses and the duration of anesthetic exposure in animals may have little relevance to clinical practice, particularly surgical anesthesia for perioperative pain. The causality underlying the observed associations between early anesthetic exposure and subsequent adverse neurodevelopmental outcomes is unknown. Anesthetic exposure may be a marker of increased risk. Especially in young children, procedures requiring general anesthesia should be performed only as necessary and general anesthesia duration should be minimized. Alternatives to general anesthesia and the deferral of elective procedures beyond the first few years of life should be considered, as appropriate. Participation in ongoing efforts should be encouraged to generate further data.
Available from: ejcts.oxfordjournals.org
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As the surgical results for Fontan candidates improve, much attention has been given to the long-term cognitive outcomes. This study aimed to assess the neurocognitive outcomes after Fontan completion, and to determine the factors associated with an extremely low intelligence quotient (IQ <70).
A total of 70 local eligible school-aged patients were enrolled in the study (hypoplastic left heart syndrome, 17; right atrial isomerism, 15 and others, 38). Fontan operations were performed at a median age of 1.8 (range, 0.5-8.9) years (primary Fontan, 4 of 70 [6%]). The Wechsler Intelligence Test was taken at a median age of 9 (range, 5.1-14.4) years for the purpose of neurocognitive evaluation. Patients' data were collected from medical records, and a retrospective analysis of potential predictors for an IQ <70 was performed.
The median full-scale IQ (FSIQ) for the entire cohort was 85 (range, 43-118). Of the lower order composites, the perceptual reasoning index and the working memory index were significantly lower in low-FSIQ patients (P < 0.05). Overall, 15 of 70 (21%) of the cohort had an IQ <70. Univariate analysis identified three significant risk factors for FSIQ <70 (15 of 70, 21%): body weight <2.5 kg at initial palliative surgery (P < 0.05), low 5-min Apgar score <4 (P < 0.05) and inter-stage events requiring cardiopulmonary resuscitation (CPR) (P < 0.05). No other patient-specific factors (e.g. cardiac morphology) or modifiable surgical factors (e.g. the use of hypothermic cardiac arrest) were associated with FSIQ <70.
Low body weight (<2.5 kg) at initial operation, low 5-min Apgar score (<4) and inter-stage CPR were significant risk factors for impaired neurocognitive outcomes. An evolving strategy for preventing inter-stage CPR may improve cognitive outcomes.
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