Objectives: To characterize the prevalence, incidence, and temporal evolution of thrombocytopenia (platelets < 100 × 109/L) in septic shock and to investigate the independent association of thrombocytopenia on clinical outcomes. Design: Retrospective, propensity-matched, cohort study. Setting: Two academic ICUs in Winnipeg, Canada. Patients: Nine-hundred eighty adult patients diagnosed with septic shock between 2007 and 2012. Interventions: Propensity-matched cohort analysis and Cox proportional hazard model evaluating thrombocytopenia over time. Measurements and Main Results: Of 980 adults, 165 patients (16.8%) had thrombocytopenia at ICU admission (prevalent), whereas 271 (27.7%) developed thrombocytopenia during ICU admission (incident). Among patients with incident thrombocytopenia, the median time from ICU admission to thrombocytopenia was 2 days (interquartile range, 1–3 d). Among survivors, the median time from incident thrombocytopenia to platelet recovery was 6 days (interquartile range, 4–8 d). The median time from liberation of vasopressors to recovery of platelets concentration (≥ 100 × 109/L) was 2 days (interquartile range, 0–4 d). In a propensity-matched analysis, thrombocytopenia was associated with increased durations of ICU length of stay (9 vs 6 d; p < 0.01), mechanical ventilation (7 vs 4 d; p < 0.01), and vasopressor use (4 vs 3 d; p < 0.01), as well as increased major bleeding events (41% vs 18%; p < 0.01). In an adjusted Cox proportional hazards model, thrombocytopenia was significantly associated with both increased ICU mortality (hazard ratio, 1.99; 95% CI, 1.51–2.63) and hospital mortality (hazard ratio, 1.93; 95% CI, 1.48–2.51). Conclusions: Both the prevalence and incidence of thrombocytopenia are high in septic shock. Incident thrombocytopenia occurs early in septic shock, and platelet recovery lags behind clinical recovery. In septic shock, thrombocytopenia is associated with increased length of stay, longer duration of organ support, major bleeding events, and mortality.

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Background: Septic shock is among the most common causes of admission to medical intensive care units (ICU) and is associated with mortality of 20-40%. The white blood cell count (WBC) at time of admission correlates with prognosis in septic shock but it is not known if the change in WBC over time (i.e. the WBC trajectory) impacts survival. Hypothesis: We hypothesized that the trajectory of the WBC count in septic shock can identify distinct clinical groups and be an independent predictor of 30-day mortality. Objectives: 1) To identify groups of patients with different WBC trajectories using group-based trajectory analysis; 2) To evaluate patient and illness factors associated with WBC count trajectories; and 3) To estimate the association of WBC trajectory with mortality in septic shock. Methods: We completed a retrospective cohort study of adult patients with septic shock admitted to an ICU in Winnipeg, Canada between 2006-2014. We used group-based trajectory analysis to analyze the trend of WBC over the first 7 days of ICU admission to group patients according to stastically similar trajectories. Group-based trajectory analysis is a statistical method that can be used to describe the pattern of a variable over time. Rather than pre-specifying groups within a population, or using methods to measure an average trajectory for the entire population, group-based trajectory analysis allows for different groups with different trajectories to emerge. We used the Bayesian Information Criterion (BIC) and clinical validity characteristics to select the optimal trajectory model. We developed a multinomial logistic regression model to evaluate the association of patient and illness factors with WBC trajectories. We constructed a multivariable Cox proportional hazard models adjusted for age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, comorbidities, infection type and antibiotics to evaluate the association of WBC trajectory on 30-day mortality. Results: Our final study cohort comprised 917 patients with septic shock. The favoured model identified 7 distinct trajectories of WBC (Figure 1). We found that only baseline platelet count and sex were associated with WBC trajectory. The 30-day mortality of the entire cohort was 26.3%, and ranged from 23.1% in group 4 to 63% in group 5 (rising WBC trajectory). In a multivariable Cox proportional hazard model, group 5 was independently associated with an increased hazard of death (Hazard Ratio 3.48, 95% CI 1.92 to 6.35, p<0.01). Conclusions: We found seven unique and clinically relevant groups of patients with septic shock using trajectory analysis of the WBC count. Routine baseline characteristics are poor predictors of trajectory group assignment. The rising WBC trajectory is associated with an increased risk of death in septic shock. Further studies are required to fully describe the clinical characteristics and prognosis associated with distinct WBC trajectories and whether this information can inform level of care decisions and anticipated response to treatments. In the era of Big Data, trajectory analysis will be broadly applicable to the field of hematology where trends in blood counts or biomarkers of disease may provide valuable clinical or prognostic information. Examples could include analysis of the M-protein trajectory in Multiple Myeloma, and the trajectory of platelet counts in immune thrombocytopenia. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

IntroductionThe aim of this paper is to provide a protocol for a systematic review assessing the effectiveness of evidence from randomised controlled trials comparing fetal alcohol spectrum disorders pharmacological and non-pharmacological interventions with placebo/dummy interventions or usual standards of care in children and adolescents (<18 years old).Methods and analysisThe following electronic databases will be searched: Medline (Ovid), Cumulative Index of Nursing and Allied Health Plus with Full text (EBSCO), Cochrane Central Register of Controlled Trials (Cochrane Library—Wiley), PsycINFO (ProQuest) and Proquest DissertationsandTheses will be searched from inception to March 2017 for relevant citations of published trials using individualised search strategies prepared for database. We will also search the reference lists of relevant articles and conference proceedings. Two reviewers will independently assess each study against predetermined inclusion/exclusion criteria and extract data including population characteristics, types and duration of interventions and outcomes from included trials. Internal validity will be assessed using the Cochrane Risk of Bias Tool. Primary outcome measures will be improvements in symptoms, including: hyperactivity, impulsivity and attention as measured by standard rating scales. Secondary outcome measures will include improvements in physical and mental health domains, as well as cognitive, behavioural, social and educational skills as measured by rating scales, standardised psychometric tests of IQ and memory, grade repetition, literacy tests and diagnosis of mental health disorder.Ethics and disseminationEthical approval will not be obtained since it is not required for systematic reviews as there are no concerns regarding patient privacy. The results of this review will be disseminated through publication in a peer-review journal and presented at relevant conferences.PROSPERO registration numberCRD42013005996.

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Purpose Septic shock is associated with a mortality of 20-40%. The white blood cell count (WBC) at hospital admission correlates with prognosis in septic shock. Here, we explore whether the trajectory of WBC after admission provides further information about outcomes. We aimed to identify groups of patients with different WBC trajectories and the association of WBC trajectory with mortality. Methods We included adult patients with septic shock in two academic intensive care units (ICU) in Winnipeg, MB, Canada between 2006 and 2012. We used group-based trajectory analysis to group patients according to their WBC patterns over the first seven days in the ICU. Our primary analysis was the association of WBC trajectory group on 30-day mortality using multivariable Cox proportional hazards regression. Results We included 917 patients with septic shock. The final model identified seven distinct WBC trajectories. The rising WBC trajectory was independently associated with increased mortality (hazard ratio, 3.41; 95% confidence interval, 1.86 to 6.26; P \ 0.001) compared with the stable WBC trajectory. Conclusion In patients with septic shock, distinct and clinically relevant groups can be identified by analyzing WBC trajectories. A rising WBC trajectory was associated with higher mortality. Re ´sumeÓbjectif Le choc septique est associe´a`une mortalite´de 20 a`40 %. La nume´ration leucocytaire a`l'admission al 'ho ˆpital est corre´le´e au pronostic en cas de choc septique. Dans ce manuscrit, nous tentons de de´terminer si l'e´volution de la nume´ration leucocytaire apre`s

IntroductionThe pathogenesis of heart failure (HF) in diabetic individuals, called “diabetic cardiomyopathy”, is only partially understood. Alterations in the cardiac autonomic nervous system due to oxidative stress have been implicated. The intrinsic cardiac nervous system (ICNS) is an important regulatory pathway of cardiac autonomic function, however, little is known about the alterations that occur in the ICNS in diabetes. We sought to characterize morphologic changes and the role of oxidative stress within the ICNS of diabetic hearts. Cultured ICNS neuronal cells from the hearts of 3- and 6-month old type 1 diabetic streptozotocin (STZ)-induced diabetic Sprague-Dawley rats and age-matched controls were examined. Confocal microscopy analysis for protein gene product 9.5 (PGP 9.5) and amino acid adducts of (E)-4-hydroxy-2-nonenal (4-HNE) using immunofluorescence was undertaken. Cell morphology was then analyzed in a blinded fashion for features of neuronal dystrophy and the presence of 4-HNE adducts.ResultsAt 3-months, diabetic ICNS neuronal cells exhibited 30% more neurite swellings per area (p = 0.01), and had a higher proportion with dystrophic appearance (88.1% vs. 50.5%; p = <0.0001), as compared to control neurons. At 6-months, diabetic ICNS neurons exhibited more features of dystrophy as compared to controls (74.3% vs. 62.2%; p = 0.0448), with 50% more neurite branching (p = 0.0015) and 50% less neurite outgrowth (p = <0.001). Analysis of 4-HNE adducts in ICNS neurons of 6-month diabetic rats demonstrated twice the amount of reactive oxygen species (ROS) as compared to controls (p = <0.001).ConclusionNeuronal dystrophy occurs in the ICNS neurons of STZ-induced diabetic rats, and accumulates temporally within the disease process. In addition, findings implicate an increase in ROS within the neuronal processes of ICNS neurons of diabetic rats suggesting an association between oxidative stress and the development of dystrophy in cardiac autonomic neurons.