Early Childhood General Anesthesia and Neurodevelopmental Outcomes in the Avon Longitudinal Study of Parents and Children Birth Cohort.

BACKGROUND: Most common anesthetic agents have been implicated in causing neurodegeneration in the developing animal brain, leading to warnings regarding their use in children. The hypothesis of this study was that exposure to general anesthesia and surgery before 4 yr would associate with adverse neurodevelopmental outcomes at age 7 to 16 yr. METHODS: This cohort study comprised 13,433 children enrolled in the Avon Longitudinal Study of Parents and Children, a prospective, population-based birth cohort born between 1991 and 1993 in southwest England. Children were grouped by none, single, or multiple exposures to general anesthesia and surgery by 4 yr. Motor, cognitive, linguistic, educational, social, and behavioral developmental outcomes were evaluated at 7 to 16 yr using school examination results, validated parent/teacher questionnaires, or clinic assessments. Continuous outcomes were z-scored. P-value thresholds were corrected using false discovery rate procedures. RESULTS: This study compared 46 neurodevelopmental outcomes in 13,433 children: 8.3% (1,110) exposed singly and 1.6% (212) exposed multiply to general anesthesia and surgery. Of these, the following reached predefined levels of statistical significance (corrected P < 0.00652): dynamic balance scores were 0.3 SD (95% CI, 0.1, 0.5; P < 0.001) lower in multiply exposed children; manual dexterity performance was 0.1 SD (95% CI, 0.0, 0.2; P = 0.006) lower in singly and 0.3 SD (95% CI, 0.1, 0.4; P < 0.001) lower in multiply exposed children; and social communication scores were 0.1 SD (95% CI, 0.0, 0.2; P = 0.001) and 0.4 SD (95% CI, 0.3, 0.5; P < 0.001) lower in singly and multiply exposed children, respectively. General anesthesia and surgery were not associated with impairments in the remaining neurodevelopmental measures including: general cognitive ability; attention; working memory; reading, spelling, verbal comprehension and expression; behavioral difficulties; or national English, mathematics, and science assessments (all ≤0.1 SD; corrected P ≥ 0.00652). CONCLUSIONS: Early childhood general anesthesia and surgery were not associated with a global picture of clinically and statistically significant neurodegenerative effects, providing reassurance about the neurotoxic potential of general anesthesia. Exposure to anesthesia and surgery was associated with significantly lower motor and social linguistic performance.

Assessing Long-term Neurodevelopmental Outcome Following General Anesthesia in Early Childhood: Challenges and Opportunities.

Neurodegeneration has been reported in young animals after exposure to all commonly used general anesthetic agents. The brain may be particularly vulnerable to anesthetic toxicity during peak synaptogenesis (in gestation and infancy). Human studies of long-term neurodevelopmental outcome following general anesthesia in early childhood report contradictory findings. This review assesses the strengths and deficiencies in human research methodologies to inform future studies. We identified 76 studies, published between 1990 and 2017, of long-term neurodevelopmental outcome following early childhood or in utero general anesthesia exposure: 49 retrospective, 9 ambidirectional, 17 prospective cohort studies, and 1 randomized controlled trial. Forty-nine studies were explicitly concerned with anesthetic-induced neurotoxicity. Full texts were appraised for methodological challenges and possible solutions. Major challenges identified included delineating effects of anesthesia from surgery, defining the timing and duration of exposure, selection of a surgical cohort and intervention, addressing multiple confounding life course factors, detecting modest neurotoxic effects with small sample sizes (median, 131 children; interquartile range, 50-372), selection of sensitive neurodevelopmental outcomes at appropriate ages for different developmental domains, insufficient length of follow-up (median age, 6 years; interquartile range, 2-12 years), and sample attrition. We discuss potential solutions to these challenges. Further adequately powered, multicenter, prospective randomized controlled trials of anesthetic-induced neurotoxicity in children are required. However, we believe that the inherent methodological challenges of studying anesthetic-induced neurotoxicity necessitate the parallel use of well-designed observational cohort studies.

Collision tumors of the thyroid: A case report and review of the literature.

BACKGROUND: Collision tumors of the thyroid are a rare pathology that present a diagnostic and treatment challenge. In this report, we present an interesting case and a review of the current literature as to inform management. METHODS AND RESULTS: An 88-year-old woman presented with acute airway compromise and vocal cord paralysis. CT identified a thyroid mass and widespread metastasis. Histopathology identified the lesion as a collision tumor consisting of a squamous cell carcinoma (SCC) and papillary thyroid carcinoma. The patient was managed with surgery and palliative radiotherapy. However, she died from complications of a lower respiratory tract infection. We also present a review of the literature with 33 cases reviewed. CONCLUSION: Management of collision tumors is complex because of the duality of the pathology. They should be managed in a multidisciplinary team setting and treatment should be patient specific. Generally, the most aggressive neoplasm should guide treatment. We recommend surgical management with adjunct therapy.

Improving access to clinical guidance: redevelopment of a junior doctor intranet page.

Junior doctors frequently rely on electronic access to clinical guidelines to inform assessment and management, particularly whilst on-call and occasionally during emergencies. Difficulties in locating and accessing up to date guidance from different hospital intranet sites can lead to delays or errors in patient management. We used a focus group and email feedback to redesign an intranet site for junior doctors which logically organised the documents which doctors said they needed access to in one readily accessible location. A quality improvement project was carried out over six months, testing two iterations of the new junior doctors' intranet site before a third version was launched and evaluated. Their performance was measured by the number of mouse clicks and the time required for doctors to find a representative subset of five guidelines, and revisions were made at each cycle based on feedback from doctors and stakeholders. Cumulatively, we demonstrated a decrease in the total number of clicks required to access the sample of guidelines from 18 to 12 clicks, a corresponding decrease in the time required to access the sample of guidelines from 130 seconds to 22 seconds, and an increase in user satisfaction. We maintained one-click access to emergency guidance. In conclusion, we have developed and implemented an electronic resource for junior doctors which provides more immediate access to both emergency and non-emergency clinical guidance. To ensure the resource remains up to date, it will be maintained by Foundation Programme representatives at our hospital on a rolling basis.

High fat feeding promotes obesity and renal inflammation and protects against post cardiopulmonary bypass acute kidney injury in swine.

INTRODUCTION: Obesity confers a survival advantage in the critically ill and in patients undergoing cardiac surgery. We explored whether an obesogenic high fat diet could confer protection against post cardiopulmonary bypass (CPB) acute kidney injury (AKI) in a swine model. METHODS: In this study, 28 anaesthetised adult female Landrace White swine (55 to 70 kg) were allocated into a 4 group design to either 2.5 hours of CPB or Sham operation with or without pre-procedural high fat (HF) feeding containing 15% lard, 1.5% cholesterol and 1% cholic acid for 12-weeks (Groups: Sham, CPB, CPB + HF and Sham + HF). Our primary endpoint was creatinine clearance measured at 1.5 and 24 hours post intervention. This is a validated index of the glomerular filtration rate (GFR) in swine and an endpoint used in our clinical studies. Secondary endpoints included measures of systemic and renal inflammation, endothelial homeostasis, tubular injury and dysfunction, and inflammatory cell signalling. Differences between groups were calculated using analysis of variance with adjustment for baseline differences for repeated measures. RESULTS: CPB in pigs fed a normal chow diet resulted in AKI. This was characterised by reductions in GFR sustained for up to 24 hours post injury relative to Sham operated pigs fed a normal diet; mean difference 50.2 ml/min (95% CI 5.9 to 94.4). Post CPB AKI was also characterised by renal inflammation, parallel activation of both pro-inflammatory (NF-kB, iNOS) and pro-survival pathways (pAkt, p70s6k, HIF-1α) and apoptosis. Pigs fed a 12-week high fat diet developed obesity and hyperlipidaemia. This was associated with increased redox sensitive pro-inflammatory and anti-apoptotic signalling, and tubular epithelial cell proliferation. High fat feeding also protected swine against post CPB AKI; mean difference in creatinine clearance CPB - CPB + HF -65.3 ml/min (95% CI -106.9 to -23.7), by preserving endothelial homeostasis and function, and preventing the reductions in GFR, loss of ATP and tubular apoptosis that characterise the extension phase of AKI in swine at 24 hours post injury. Reno-protection was not attributed to pAkt signaling. CONCLUSIONS: A high fat diet promoted obesity and renal inflammation and prevented post CPB AKI in swine. This study provides insights into the obesity paradox and the failure of anti-inflammatory interventions to improve clinical outcomes in patients at risk of post cardiac surgery AKI.

Increased perioperative mortality following aprotinin withdrawal: a real-world analysis of blood management strategies in adult cardiac surgery.

PURPOSE: To evaluate the effect of aprotinin withdrawal in 2008 on patient outcomes, to assess the likely risks and benefits of its re-introduction, and to consider the relevance of existing evidence from clinical trials to 'real-world' practice. METHODS: We performed a nested case-control study of two cohorts undergoing adult cardiac surgery in a single tertiary centre. The first group underwent surgery between 1 January 2005 and 30 July 2007 (n = 3,578), prior to aprotinin withdrawal; the second group underwent surgery between 1 January 2009 and 31 December 2010 (n = 3,030), after aprotinin withdrawal. Propensity matching was used to select patients matched for 24 covariates in both groups (n = 3,508). We also estimated the effect of aprotinin withdrawal on a subgroup of high-risk patients (n = 1,002). Results were expressed as adjusted odds ratios (OR) and 95% confidence intervals (CI) for categorical data and hazard ratios (HR) for time-to-event data. RESULTS: In propensity-matched cohorts, the withdrawal of aprotinin from clinical use was associated with more bleeding, higher rates of emergency re-sternotomy, OR 2.10 (1.04-4.25), and acute kidney injury (AKI), OR 1.86 (1.53-2.25). In high-risk patients, the increases in bleeding and AKI following aprotinin withdrawal were of a greater magnitude. Aprotinin withdrawal was also associated with a significant increase in 30-day mortality, HR 2.51 (1.00-6.29), in the high-risk group. The results were not altered by sensitivity analyses that adjusted for potential selection bias, time series bias and unmeasured confounders. CONCLUSIONS: Aprotinin withdrawal was associated with increased complication rates and patient deaths following cardiac surgery. These real-world findings are at odds with those of randomised trials and cohort studies that have considered the clinical role of aprotinin.

Interactions of cardiopulmonary bypass and erythrocyte transfusion in the pathogenesis of pulmonary dysfunction in Swine.

BACKGROUND: Allogeneic erythrocyte transfusion in cardiac surgical patients is associated with a fourfold increase in pulmonary complications. Our understanding of the processes underlying these observations is poor and there is no experimental model of transfusion-related acute lung injury that shows homology to cardiac surgical patients. Our objective was to develop a novel swine recovery model to determine how two clinical risk factors, allogenic erythrocyte transfusion and cardiopulmonary bypass, interact in the genesis of postcardiac surgery acute lung injury. METHODS: Thirty-six pigs were infused with allogeneic 14- or 42-day-old erythrocytes or they underwent cardiopulmonary bypass with or without transfusion of 42-day erythrocyte. Controls received saline. All pigs were recovered and assessed for pulmonary dysfunction, inflammation, and endothelial activation at 24 h. RESULTS: Transfusion of stored allogeneic erythrocytes in pigs compared with sham caused pulmonary dysfunction characterized by reduced lung compliance (mean difference -3.36 [95% CI, -5.31 to -1.42] ml/cm H2O), an increase in protein levels in bronchoalveolar lavage fluid, histological lung injury inflammation, and endothelial activation. Transfusion of blood stored for up to 42 days resulted in greater protein levels in bronchoalveolar lavage fluid, macrophage infiltration, platelet activation, and depletion of T-lymphocytes in recipient lungs versus 14-day-old blood. Transfusion interacted with cardiopulmonary bypass to increase lung injury in the absence of platelet activation. CONCLUSIONS: In this novel large animal model of allogeneic erythrocyte transfusion, pulmonary dysfunction occurs in the absence of any priming event, is increased when combined with other inflammatory stimuli, and is mediated by monocyte activation and T-lymphocyte depletion.