Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection.

Cystic fibrosis (CF) is caused by mutations of the gene encoding the CF transmembrane conductance regulator. It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment. We sought to characterize the peripheral immune signatures in CF and its association with clinical phenotypes. Healthy peripheral blood mononuclear cells (PBMCs) were cultured with plasma from CF probands (CFPs) or healthy control subjects (HCs) followed by nCounter gene and microRNA (miRNA) profiling. A discovery cohort of 12 CFPs and 12 HCs and a validation cohort of 103 CFPs and 31 HCs (our previous microarray data [GSE71799]) were analyzed to characterize the composition of cultured immune cells and establish a miRNA‒mRNA network. Cell compositions and miRNA profiles were associated with clinical characteristics of the cohorts. Significantly differentially expressed genes and abundance of myeloid cells were downregulated in PMBCs after culture with CF plasma (P < 0.05). Top-ranked miRNAs that increased in response to CF plasma (adjusted P < 0.05) included miR-155 and miR-146a, which target many immune-related genes, such as IL-8. Pseudomonas aeruginosa infection was negatively associated with abundance of monocytes and the presence of those regulatory miRNAs. Extrinsic signals in plasma from patients with CF led to monocyte inactivation and miRNA upregulation in PBMCs. An improved understanding of the immune effects of extrinsic factors in CF holds great promise for integrating immunomodulatory cell therapies into current treatment strategies in CF.

Hemodynamic Profile of Acute Kidney Injury Following the Fontan Procedure: Impact of Renal Perfusion Pressure.

BACKGROUND: Acute kidney injury (AKI) is common following cardiopulmonary bypass. Fontan completion may result in systemic venous hypertension and low cardiac output, reducing renal perfusion pressure (RPP) and further increasing the risk of AKI. We investigated the incidence and risk factors for post-Fontan AKI. METHODS: Single-center retrospective study of children undergoing Fontan completion from 2005 to 2012. Demographic and hemodynamic variables were assessed for association with AKI. Subgroup analysis was performed on patients with high-grade AKI (creatinine increase of ≥2.0 × baseline). Vital sign data were collected hourly for the first postoperative day. RESULTS: A total of 186 patients underwent Fontan at 3.1 (2.5-3.8) years of age and 13.5 kg (12.2-15.1). Acute kidney injury occurred in 97 (52%) patients, with high-grade AKI in 52 (28%). Univariate analysis identified reduced RPP in patients with AKI compared to those without AKI, 50 (45-56) mm Hg versus 58 (54-61) mm Hg ( P < .0001), due to lower mean arterial blood pressure, 63 (60-69) versus 70 (66-73) mm Hg ( P < .0001), and higher central venous pressure, 14 (12-16) versus 13 (11-14) mm Hg, ( p < .0001). Multivariable logistic regression and classification tree analyses further identified elements of RPP as significant predictors of AKI, especially high-grade AKI. Postoperative intubation was linked to AKI development. Patients with AKI had decreased postoperative urine output with increased colloid requirements, duration of chest tube insertion, and hospital length of stay. CONCLUSION: Acute kidney injury occurs frequently following the Fontan procedure. Associated factors include reduced RPP, high colloid requirements, and postoperative intubation. Targeted hemodynamic interventions may serve to reduce the incidence of post-Fontan AKI.

A Pilot Study of Antithrombin Replacement Prior to Cardiopulmonary Bypass in Neonates.

Neonates have low levels of antithrombin. Inadequate anticoagulation during cardiopulmonary bypass (CPB) due to low antithrombin activity may result in a poor preservation of the coagulation system during bypass. We hypothesize that antithrombin replacement to neonates prior to CPB will preserve the hemostatic system and result in less postoperative bleeding. A randomized, double-blinded, placebo-controlled pilot study of antithrombin replacement to neonates prior to CPB was conducted. Preoperative antithrombin levels determined the dose of recombinant antithrombin or placebo to be given. Antithrombin levels were measured following the dosing of the antithrombin/placebo, after initiation of bypass, near the completion of bypass, and upon intensive care unit admission. Eight subjects were enrolled. No subject had safety concerns. Mediastinal exploration occurred in two antithrombin subjects and one placebo subject. Antithrombin activity levels were significantly higher in the treated group following drug administration; levels continued to be higher than preoperatively but not different from the placebo group at all other time points. Total heparin administration was less in the antithrombin group; measurements of blood loss were similar in both groups. A single dose of recombinant antithrombin did not maintain 100% activity levels throughout the entire operation. Although no safety concerns were identified in this pilot study, a larger trial is necessary to determine clinical efficacy.

Changes in cerebral oxygen saturation correlate with S100B in infants undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVES: The relationship of cerebral saturation measured by near-infrared spectroscopy with serum biomarker of brain injury S100B was investigated in infants undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective cohort study. SETTING: Single-center children's hospital. PATIENTS: Forty infants between 1 and 12 months old weighing greater than or equal to 4 kg with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum S100B was measured at eight time points over 72 hours using enzyme-linked immunosorbent assay. Physiologic data including arterial, cerebral, and somatic regional oxygen saturations measured by near-infrared spectroscopy were synchronously recorded at 1-minute intervals from anesthesia induction through 72 postoperative hours. The arterial-cerebral oxygen saturation difference was calculated as the difference between arterial saturation and cerebral regional saturation. Thirty-eight patients, 5.4 ± 2.5 months old, were included in the analysis; two were excluded due to the use of postoperative extracorporeal membrane oxygenation. Seventeen patients (44.7%) had preoperative cyanosis. S100B increased during cardiopulmonary bypass in all patients, from a median preoperative baseline of mean ± SE: 0.055 ± 0.038 to a peak of 0.610 ± 0.038 ng/mL, p less than 0.0001. Patients without preoperative cyanosis had a higher S100B peak at the end of cardiopulmonary bypass. Although the absolute cerebral regional saturation on cardiopulmonary bypass was not associated with S100B elevation, patients who had arterial-cerebral oxygen saturation difference greater than 50 at any time during cardiopulmonary bypass had a higher S100B peak (mean ± SE: 1.053 ± 0.080 vs 0.504 ± 0.039 ng/mL; p < 0.0001). CONCLUSIONS: A wide cerebral arteriovenous difference measured by near-infrared spectroscopy during cardiopulmonary bypass is associated with increased serum S100B in the perioperative period and may be a modifiable risk factor for neurological injury.

A human factors framework and study of the effect of nursing workload on patient safety and employee quality of working life.

BACKGROUND: Nursing workload is increasingly thought to contribute to both nurses' quality of working life and quality/safety of care. Prior studies lack a coherent model for conceptualising and measuring the effects of workload in healthcare. In contrast, we conceptualised a human factors model for workload specifying workload at three distinct levels of analysis and having multiple nurse and patient outcomes. METHODS: To test this model, we analysed results from a cross-sectional survey of a volunteer sample of nurses in six units of two academic tertiary care paediatric hospitals. RESULTS: Workload measures were generally correlated with outcomes of interest. A multivariate structural model revealed that: the unit-level measure of staffing adequacy was significantly related to job dissatisfaction (path loading=0.31) and burnout (path loading=0.45); the task-level measure of mental workload related to interruptions, divided attention, and being rushed was associated with burnout (path loading=0.25) and medication error likelihood (path loading=1.04). Job-level workload was not uniquely and significantly associated with any outcomes. DISCUSSION: The human factors engineering model of nursing workload was supported by data from two paediatric hospitals. The findings provided a novel insight into specific ways that different types of workload could affect nurse and patient outcomes. These findings suggest further research and yield a number of human factors design suggestions.