Intraoperative Blood Pressure and Long-Term Neurodevelopmental Function in Children Undergoing Ambulatory Surgery.

BACKGROUND: Some studies have found surgery and anesthesia in children to be associated with neurodevelopmental deficits, but specific reasons for this association have not been fully explored. This study evaluates intraoperative mean arterial pressure (MAP) during a single ambulatory procedure in children and subsequent mental disorder diagnoses. METHODS: A retrospective observational study was performed including children ≥28 days and <18 years of age with intraoperative electronic anesthetic records between January 1, 2009, and April 30, 2017, at our institution. Eligible children were categorized based on their mean intraoperative MAP relative to other children of the same sex and similar age: category 1 (very low): children with mean intraoperative MAP values below the 10th percentile, category 2 (low): mean MAP value ≥10th and <25th percentiles, category 3 (reference): mean MAP value ≥25th and <75th percentiles, category 4 (high): mean MAP value ≥75th and <90th percentile, and category 5 (very high): mean MAP value ≥90th percentile. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) and ICD, Tenth Revision, Clinical Modification (ICD-10)-coded mental disorders were identified in hospital and outpatient claims, with a median duration of follow-up after surgery of 120 days (interquartile range [IQR], 8-774.5 days). Cox proportional hazards models evaluated the hazard ratio (HR) of time to first mental disorder diagnosis associated with intraoperative blood pressure category between the end of surgery and censoring, with the primary analysis adjusting for demographic, anesthetic, comorbidity, and procedure-type variables as potential confounders. RESULTS: A total of 14,724 eligible children who received general anesthesia for a single ambulatory surgical procedure were identified. After adjusting for all available potential confounders, when compared to the reference, there were no statistically significant differences in mental disorder diagnosis risk based on intraoperative mean MAP category. Compared to reference, children in the very low and low blood pressure categories reported HRs of 1.00 (95% confidence interval [CI], 0.74-1.35) and 1.10 (95% CI, 0.87-1.41) for a mental disorder diagnosis, respectively, and children in the high and very high categories reported HRs of 0.87 (95% CI, 0.68-1.12) and 0.76 (95% CI, 0.57-1.03), respectively. CONCLUSIONS: Presence in a predefined mean intraoperative MAP category was not associated with subsequent mental disorder diagnoses within our follow-up period. However, the limitations of this study, including uncertainty regarding what constitutes an adequate blood pressure in children, may limit the ability to form definitive conclusions.

Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes: A Systematic Review and Meta-analysis.

Importance: Clinical studies of neurodevelopmental outcomes after anesthetic exposure have evaluated a range of outcomes with mixed results. Objective: To examine via meta-analyses the associations between exposure to general anesthesia and domain-specific neurodevelopmental outcomes in children. Data Sources: PubMed/MEDLINE, Embase, CINAHL, Web of Science and the Cochrane Library were searched from inception to August 31, 2021. Study Selection: Inclusion criteria were exposures to procedures requiring general anesthesia at younger than 18 years and evaluation of long-term neurodevelopmental function after exposure. Studies lacking unexposed controls or focused on children with major underlying comorbidities were excluded. Data Extraction and Synthesis: Extracted variables included effect size; hazard, risk, or odds ratio; number of exposures; procedure type; major comorbidities; age of exposure and assessment; presence of unexposed controls; and study design. Studies were independently reviewed by 2 coders, and review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model. Main Outcomes and Measures: The main outcomes were standardized mean differences (SMD) for scores in the neurodevelopmental domains of academics, behavioral problems, cognition, executive function, general development, language, motor function, nonverbal reasoning, social cognition, and hazard and risk of neurodevelopmental disorder diagnoses. Results: A total of 31 studies contributed data for meta-analysis. For each of the assessed neurodevelopmental domains, the numbers of children evaluated ranged from 571 to 63 315 exposed and 802 to 311 610 unexposed. Children with any exposure (single or multiple) had significantly worse behavioral problems scores, indicating more behavioral problems (SMD, -0.10; 95% CI, -0.18 to -0.02; P = .02), and worse scores in academics (SMD, -0.07; 95% CI -0.12 to -0.01; P = .02), cognition (SMD, -0.03; 95% CI, -0.05 to 0.00; P = .03), executive function (SMD, -0.20; 95% CI, -0.32 to -0.09; P < .001), general development (SMD, -0.08; 95% CI, -0.13 to -0.02; P = .01), language (SMD, -0.08; 95% CI, -0.14 to -0.02; P = .01), motor function (SMD, -0.11; 95% CI, -0.21 to -0.02; P = .02), and nonverbal reasoning (SMD, -0.15; 95% CI, -0.27 to -0.02; P = .02). Higher incidences of neurodevelopmental disorder diagnoses were also reported (hazard ratio, 1.19; 95% CI, 1.09 to 1.30; P < .001; risk ratio, 1.81; 95% CI, 1.25 to 2.61; P = .002). Conclusions and Relevance: These findings support the hypothesis that associations between anesthetic exposure during childhood and subsequent neurodevelopmental deficits differ based on neurodevelopmental domain.

The pro-domains of neurotrophins, including BDNF, are linked to Alzheimer's disease through a toxic synergy with Aß.

Brain-derived neurotrophic factor (BDNF) has a crucial role in learning and memory by promoting neuronal survival and modulating synaptic connectivity. BDNF levels are lower in the brains of individuals with Alzheimer's disease (AD), suggesting a pathogenic involvement. The Drosophila orthologue of BDNF is the highly conserved Neurotrophin 1 (DNT1). BDNF and DNT1 have the same overall protein structure and can be cleaved, resulting in the conversion of a full-length polypeptide into separate pro- and mature-domains. While the BDNF mature-domain is neuroprotective, the role of the pro-domain is less clear. In flies and mammalian cells, we have identified a synergistic toxic interaction between the amyloid-ß peptide (Aß1-42) and the pro-domains of both DNT1 and BDNF. Specifically, we show that DNT1 pro-domain acquires a neurotoxic activity in the presence of Aß1-42. In contrast, DNT1 mature-domain is protective against Aß1-42 toxicity. Likewise, in SH-SY5Y cell culture, BDNF pro-domain is toxic only in the presence of Aß1-42. Western blots indicate that this synergistic interaction likely results from the Aß1-42-induced upregulation of the BDNF pro-domain receptor p75(NTR). The clinical relevance of these findings is underlined by a greater than thirty fold increase in the ratio of BDNF pro- to mature-domains in the brains of individuals with AD. This unbalanced BDNF pro:mature-domain ratio in patients represents a possible biomarker of AD and may offer a target for therapeutic intervention.