Two months outcomes following delirium in the pediatric intensive care unit.

The lasting consequences of delirium in children are not well characterized. This study aimed to compare the two-month outcomes in pediatric intensive care unit (PICU) survivors according to the presence of delirium. Post-hoc analysis of a single-center prospective study of mechanically ventilated (invasive ventilation or non-invasive ventilation) children followed at the CHU Sainte-Justine PICU follow-up clinic two months after PICU discharge, between October 2018 and August 2022. Delirium was defined as one or more Cornell Assessment of Pediatric Delirium (CAPD) scores ≥ 9. Primary outcome was survivors' quality of life and secondary outcomes were sleep and posttraumatic stress and anxiety and depression in parents. Multivariable linear and logistic regression models assessed the independent associations between delirium and outcomes while adjusting for age, sex, comorbidity, diagnosis, severity of illness, PICU length of stay, and invasive mechanical ventilation. Of the 179 children included over a 47 month-period, 117 (65.4%) had delirium. Children with delirium were more commonly intubated (91.5% vs. 30.7%, p < 0.001) and had higher PELOD-2 scores (10 vs. 4, p < 0.001). On multivariable analysis, delirium was associated with a decreased quality of life at 2.3 months post discharge (p = 0.03). The severity of the delirium episode (higher scores of CAPD) was associated with a higher likelihood of sleep disturbances (OR 1.13, p = 0.01) and parental anxiety (OR 1.16, p = 0.01), in addition to lower quality of life (p = 0.03).Conclusions: Two months following their PICU stay, children with delirium had a lower quality of life, suggesting a lasting effect of delirium on children and their families.

Iron Deficiency in Anemic Children Surviving Critical Illness: Post Hoc Analysis of a Single-Center Prospective Cohort in Canada, 2019-2022.

OBJECTIVES: Many children leave the PICU with anemia. The mechanisms of post-PICU anemia are poorly investigated, and treatment of anemia, other than blood, is rarely started during PICU. We aimed to characterize the contributions of iron depletion (ID) and/or inflammation in the development of post-PICU anemia and to explore the utility of hepcidin (a novel iron marker) at detecting ID during inflammation. DESIGN: Post hoc analysis of a single-center prospective study (November 2019 to September 2022). SETTING: PICU, quaternary center, Canada. PATIENTS: Children admitted to PICU with greater than or equal to 48 hours of invasive or greater than or equal to 96 hours of noninvasive ventilation. We excluded patients with preexisting conditions causing anemia or those admitted after cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hematological and iron profiles were performed at PICU discharge on 56 participants of which 37 (37/56) were diagnosed with anemia. Thirty-three children (33/56; 59%) were younger than 2 years. Median Pediatric Logistic Organ Dysfunction score was 11 (interquartile range, 6-16). Twenty-four of the 37 anemic patients had repeat bloodwork 2 months post-PICU. Of those, four (4/24; 16%) remained anemic. Hematologic profiles were categorized as: anemia of inflammation (AI), iron deficiency anemia (IDA), IDA with inflammation, and ID (low iron stores without anemia). Seven (7/47; 15%) had AI at discharge, and one had persistent AI post-PICU. Three patients (3/47; 6%) had IDA at discharge; of which one was lost to follow-up and the other two were no longer anemic but had ID post-PICU. Eleven additional patients developed ID post-PICU. In the exploratory analysis, we identified a diagnostic cutoff value for ID during inflammation from the receiver operating characteristic curve for hepcidin of 31.9 pg/mL. This cutoff would increase the detection of ID at discharge from 6% to 34%. CONCLUSIONS: The burden of ID in children post-PICU is high and better management strategies are required. Hepcidin may increase the diagnostic yield of ID in patients with inflammation.

Elevated Diaphragmatic Tonic Activity in PICU Patients: Age-Specific Definitions, Prevalence, and Associations.

OBJECTIVES: Tonic diaphragmatic activity (tonic Edi, i.e., sustained diaphragm activation throughout expiration) reflects diaphragmatic effort to defend end-expiratory lung volumes. Detection of such elevated tonic Edi may be useful in identifying patients who need increased positive end-expiratory pressure. We aimed to: 1) identify age-specific definitions for elevated tonic Edi in ventilated PICU patients and 2) describe the prevalence and factors associated with sustained episodes of high tonic Edi. DESIGN: Retrospective study using a high-resolution database. SETTING: Single-center tertiary PICU. PATIENTS: Four hundred thirty-one children admitted between 2015 and 2020 with continuous Edi monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We characterized our definition of tonic Edi using data from the recovery phase of respiratory illness (i.e., final 3 hr of Edi monitoring, excluding patients with significant persistent disease or with diaphragm pathology). High tonic Edi was defined as population data exceeding the 97.5th percentile, which for infants younger than 1 year was greater than 3.2 µV and for older children as greater than 1.9 µV. These thresholds were then used to identify patients with episodes of sustained elevated tonic Edi in the first 48 hours of ventilation (acute phase). Overall, 62 of 200 (31%) of intubated patients and 138 of 222 (62%) of patients on noninvasive ventilation (NIV) had at least one episode of high tonic Edi. These episodes were independently associated with the diagnosis of bronchiolitis (intubated patients: adjusted odds [aOR], 2.79 [95% CI, 1.12-7.11]); NIV patients: aOR, 2.71 [1.24-6.0]). There was also an association with tachypnea and, in NIV patients, more severe hypoxemia. CONCLUSIONS: Our proposed definition of elevated tonic Edi quantifies abnormal diaphragmatic activity during expiration. Such a definition may help clinicians to identify those patients using abnormal effort to defend end-expiratory lung volume. In our experience, high tonic Edi episodes are frequent, especially during NIV and in patients with bronchiolitis.

Impact of Blood Sampling on Anemia in the PICU: A Prospective Cohort Study.

OBJECTIVES: Fifty percent of children are anemic after a critical illness. Iatrogenic blood testing may be a contributor to this problem. The objectives of this study were to describe blood sampling practice in a PICU, determine patient factors associated with increased sampling, and examine the association among blood sampling volume, anemia at PICU discharge, and change in hemoglobin from PICU entry to PICU discharge. DESIGN: Prospective observational cohort study. SETTING: PICU of Sainte-Justine University Hospital. PATIENTS: All children consecutively admitted during a 4-month period. MEASUREMENTS AND MAIN RESULTS: Four hundred twenty-three children were enrolled. Mean blood volume sampled was 3.9 (±19) mL/kg/stay, of which 26% was discarded volume. Children with central venous or arterial access were sampled more than those without access (p < 0.05). Children with sepsis, shock, or cardiac surgery were most sampled, those with a primary respiratory diagnosis; the least (p < 0.001). We detected a strong association between blood sample volume and mechanical ventilation (H, 81.35; p < 0.0001), but no association with severity of illness (Worst Pediatric Logistic Organ Dysfunction score) (R, -0.044; p = 0.43). Multivariate analysis (n = 314) showed a significant association between the volume of blood sampled (as continuous variable) and anemia at discharge (adjusted OR, 1.63; 95% CI, 1.18-2.45; p = 0.003). We lacked power to detect an association between blood sampling and change in hemoglobin from PICU admission to PICU discharge. CONCLUSIONS: Diagnostic blood sampling in PICU is associated with anemia at discharge. Twenty-five percent of blood losses from sampling is wasted. Volumes are highest for patients with sepsis, shock, or cardiac surgery, and in patients with vascular access or ventilatory support.

Evolution of inspiratory muscle function in children during mechanical ventilation.

BACKGROUND: There is no universally accepted method to assess the pressure-generating capacity of inspiratory muscles in children on mechanical ventilation (MV), and no study describing its evolution over time in this population. METHODS: In this prospective observational study, we have assessed the function of the inspiratory muscles in children on various modes of MV. During brief airway occlusion maneuvers, we simultaneously recorded airway pressure depression at the endotracheal tube (ΔPaw, force generation) and electrical activity of the diaphragm (EAdi, central respiratory drive) over five consecutive inspiratory efforts. The neuro-mechanical efficiency ratio (NME, ΔPaw/EAdimax) was also computed. The evolution over time of these indices in a group of children in the pediatric intensive care unit (PICU) was primarily described. As a secondary objective, we compared these values to those measured in a group of children in the operating room (OR). RESULTS: In the PICU group, although median NMEoccl decreased over time during MV (regression coefficient - 0.016, p = 0.03), maximum ΔPawmax remained unchanged (regression coefficient 0.109, p = 0.50). Median NMEoccl at the first measurement in the PICU group (after 21 h of MV) was significantly lower than at the only measurement in the OR group (1.8 cmH2O/µV, Q1-Q3 1.3-2.4 vs. 3.7 cmH2O/µV, Q1-Q3 3.5-4.2; p = 0.015). Maximum ΔPawmax in the PICU group was, however, not significantly different from the OR group (35.1 cmH2O, Q1-Q3 21-58 vs. 31.3 cmH2O, Q1-Q3 28.5-35.5; p = 0.982). CONCLUSIONS: The function of inspiratory muscles can be monitored at the bedside of children on MV using brief airway occlusions. Inspiratory muscle efficiency was significantly lower in critically ill children than in children undergoing elective surgery, and it decreased over time during MV in critically ill children. This suggests that both critical illness and MV may have an impact on inspiratory muscle efficiency.

PICU Follow-Up Clinic: Patient and Family Outcomes 2 Months After Discharge.

OBJECTIVES: Hospitalization in a PICU is a life-altering experience for children and their families. Yet, little is known about the well-being of these children after their discharge. We are describing the outcome of PICU survivors at a PICU clinic 2 months after discharge. DESIGN: Prospective cohort study. SETTING: PICU and PICU clinic of CHU Sainte-Justine. PATIENTS: Prospective cohort study of children admitted for greater than or equal to 4 days, greater than or equal to 2 days of invasive ventilation, odds ratio greater than or equal to 4 days of noninvasive ventilation at Centre Hospitalier Universitaire Sainte-Justine. PATIENTS: Prospective cohort study of children admitted for greater than or equal to 4 days, greater than or equal to 2 days of invasive ventilation, or greater than or equal to 4 days of noninvasive ventilation at Centre Hospitalier Universitaire Sainte-Justine PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated by a pediatric intensivist 2 months after discharge at the follow-up clinic. They were asked to fill out validated questionnaires. One hundred thirty-two patients were followed from October 2018 to September 2020. The PICU diagnoses were respiratory illness (40.9%), head trauma, and septic shock (7.6%). Average length of PICU stay was 28.5 ± 84.2 days (median 7 d). Sixty-one percent were intubated. Symptoms reported by families were as follows: fatigue (9.9%), sleep disturbances (20.5%), feeding difficulties (12.1%), and voice change and/or stridor (9.8%). Twenty-one percent of school-aged children reported school delays. Twenty-seven children demonstrated communication delays, 45% gross motor function delays, 41% fine motor delays, 37% delays in problem-solving, and 49% delays in personal-social functioning. Quality of Life scores were 78.1 ± 20.5 and 80.0 ± 17.5 for physical and psychosocial aspects, respectively. Fourteen percent of parents reported financial difficulties, 42% reported symptoms of anxiety, 29% symptoms of depression. CONCLUSIONS: PICU survivors and their families experience significant physical and psychosocial morbidities after their critical illness. PICU follow-up is crucial to determine the outcome of these children and develop interventions.

Automated Multireplicate Quantification of Persistent HIV-1 Viremia in Individuals on Antiretroviral Therapy.

Clearance of low-level viremia that persists in most HIV-1-positive individuals on antiretroviral therapy (ART) is an important milestone for efforts to cure HIV-1 infection. The level of persistent viremia on ART is generally below the lower limit of quantification (LOQ) of current FDA-cleared plasma HIV-1 RNA assays (20 to 40 copies/ml) but can be quantified by reverse transcriptase PCR (RT-PCR) assays with single-copy sensitivity. Such assays require multistep manual methods, and their low throughput limits the capacity to monitor the effects of interventions on persistent viremia. Recently, S. Bakkour, X. Deng, P. Bacchetti, E. Grebe, et al. (J Clin Microbiol 58:e01400-20, 2020, https://doi.org/10.1128/JCM.01400-20), reported the use of multiple replicates and Poisson statistics to infer HIV-1 RNA concentrations below the commercial LOQ of an automated platform (Hologic Panther Aptima). Here, we evaluate the detection and quantitation of low-level viremia using the following two adaptions of the automated platform: a multireplicate strategy (9×) and a concentrated single-replicate strategy in which 5 ml of plasma is concentrated by centrifugation (1×, concentrated). We compare these new methods to a recently reported manual integrase-targeting single-copy assay version 2 (iSCA v2). Using laboratory-generated HIV-1 RNA plasma samples at known concentrations, all three methods had similar sensitivity for HIV-1 RNA detection, although iSCA v2 was most sensitive (95% LOD, 2.3 copies/ml), 9× was marginally less sensitive (95% LOD, 3.0 copies/ml), and 1×, concentrated was least sensitive (95% LOD, 3.9 copies/ml). In contrast, for clinical plasma samples, 9× had greater sensitivity than iSCA v2 (82% of samples were quantifiable compared with 62% of samples by iSCA v2). These results support 9× as an acceptable high-throughput alternative to iSCA v2 for quantifying low-level viremia in individuals on ART.

Performance Characteristics of a High-Throughput Automated Transcription-Mediated Amplification Test for SARS-CoV-2 Detection.

The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus has imposed severe challenges on laboratories in their effort to achieve sufficient diagnostic testing capability for identifying infected individuals. In this study, we report the analytical and clinical performance characteristics of a new, high-throughput, fully automated nucleic acid amplification test system for the detection of SARS-CoV-2. The assay utilizes target capture, transcription-mediated amplification, and acridinium ester-labeled probe chemistry on the automated Panther system to directly amplify and detect two separate target sequences in the open reading frame 1ab (ORF1ab) region of the SARS-CoV-2 RNA genome. The probit 95% limit of detection of the assay was determined to be 0.004 50% tissue culture infective dose (TCID50)/ml using inactivated virus and 25 copies/ml (c/ml) using synthetic in vitro transcript RNA targets. Analytical sensitivity (100% detection) was confirmed to be 83 to 194 c/ml using three commercially available SARS-CoV-2 nucleic acid controls. No cross-reactivity or interference was observed with testing of six related human coronaviruses, as well as 24 other viral, fungal, and bacterial pathogens, at high titers. Clinical nasopharyngeal swab specimen testing (n = 140) showed 100%, 98.7%, and 99.3% positive, negative, and overall agreement, respectively, with a validated reverse transcription-PCR nucleic acid amplification test (NAAT) for SARS-CoV-2 RNA. These results provide validation evidence for a sensitive and specific method for pandemic-scale automated molecular diagnostic testing for SARS-CoV-2.

Aeromedical Transport in Children: A Descriptive Analysis of 96 Cases.

OBJECTIVE: Pediatric aeromedical transport (AT) is highly challenging. We aim to describe a series of 96 cases of children requiring medical transport in terms of the indication, modalities, and related adverse events. METHODS: In this single-center retrospective study, we included air-transported patients less than 18 years old. RESULTS: During the study period, 96 patients, with median age of 120 months (range, 0-204), were air transported. The reason for AT was repatriation to the home country from another hospital in 65 (67.7%), whereas for 31 (32.3%) patients, it was for transport from a hospital to another for a special procedure. The main diagnosis was trauma surgery (n = 38; 39.5%). Fifteen (15.6%) patients were mechanically ventilated. No patient sustained serious adverse events during the flight. Patients were transported by an air ambulance or by a scheduled aircraft in 55.2% and 44.8%, respectively. The median flight distance was 822 km (range, 277-9878), and most of the ATs were intra-European (n = 41; 42.7%). CONCLUSION: This study describes an international experience in providing AT services for pediatric clinical cases. Among pediatric patients, the younger ones constitute a specific population, and most of them require mechanical ventilation. Therefore, the transport of these patients seems to be more appropriate in a dedicated air ambulance.

Red Blood Cell Transfusion in the Postoperative Care of Pediatric Cardiac Surgery: Survey on Stated Practice.

The optimal red blood cell transfusion threshold for postoperative pediatric cardiac surgery patients is unknown. This study describes the stated red blood cell transfusion practice of physicians who treat postoperative pediatric cardiac surgery patients in intensive care units. A scenario-based survey was sent to physicians involved in postoperative intensive care of pediatric cardiac surgery patients in all Canadian centers that perform such surgery. Respondents reported their red blood cell transfusion practice in four postoperative scenarios: acyanotic or cyanotic cardiac lesion, in a neonate or an infant. In part A of each scenario, the patient was critically ill, but stabilized; in part B, the patient became unstable. Response rate was 58 % (71 of 123), with 45 respondents indicating direct involvement in postoperative intensive care. There was a wide variability in stated transfusion threshold, ranging from <7.0-14.0 g/dL for stabilized cases. There was no significant difference between neonates and infants in stated transfusion threshold. The mean hemoglobin level below which respondents would transfuse a stabilized patient was 9 g/dL for acyanotic and 11.2 g/dL for cyanotic patients, a statistically significant difference (2.2 ± 0.9 g/dL, p < 0.001). All clinical determinants of instability significantly increased transfusion threshold. Hemodynamic instability increased transfusion threshold by 2.3 ± 1.3 g/dL in acyanotic patients and by 1.3 ± 1.1 g/dL in cyanotic patients. Cyanotic lesion and clinical instability, but not patient age, increased stated red blood cell transfusion threshold. Significant variation in reported red blood cell transfusion practice exists among physicians treating pediatric patients in intensive care following cardiac surgery.

Anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts and epithelial cells.

PURPOSE: To determine the ocular anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist (SEGRA) in primary human conjunctival fibroblasts and epithelial cells. METHODS: Two primary human conjunctival cell types, human conjunctival epithelial cells (HConEpiC) and human conjunctival fibroblasts (HConF), were challenged with interleukin-4 (IL-4) or IL-13 plus tumor necrosis factor-alpha (TNF-α). Luminex technology was used to profile the resulting inflammatory response. The effects of mapracorat on the release of eotaxin and regulated on activation, normal T cell expressed and secreted (RANTES), two allergy-related chemokines, as well as proinflammatory cytokines and intercellular adhesion molecule 1 (ICAM-1) were then determined. Small interfering RNA was used to determine whether the effects of mapracorat were mediated via the glucocorticoid receptor (GR). Dexamethasone was used as the control. RESULTS: IL-13 or IL-4 plus TNF-α in the HConF or HConEpiC significantly increased eotaxin-1 (HConF only), eotaxin-3, RANTES, multiple proinflammatory cytokines, and ICAM-1. Synergistic effects of IL-13 or IL-4 plus TNF-α were observed in the HConEpiC for RANTES and monocyte chemoattractant protein-1, and in the HConF for eotaxin-1, eotaxin-3, and RANTES. Mapracorat significantly reduced IL-4 or IL-13 plus TNF-α-induced cytokine release and ICAM-1 protein in a dose-dependent manner in both cell types, with comparable efficacy to dexamethasone. These effects were mediated through the glucocorticoid receptor (GR), as demonstrated by the reversal of inhibitory effects after silencing of glucocorticoid receptor expression. CONCLUSIONS: Data from these in vitro models indicate that mapracorat is efficacious and potent in reducing IL-4 or IL-13 plus TNF-α-induced release of allergy-related and proinflammatory cytokines from the HConF and the HConEpiC, supporting clinical evaluation of the compound in reducing allergic and inflammatory reactions in allergic conjunctivitis.

Sensitive detection assays for influenza RNA do not reveal viremia in US blood donors.

BACKGROUND: There have been anecdotal reports of influenza viremia since the 1960s. We present an assessment of the prevalence of seasonal and 2009 H1N1 influenza viremia (via RNA testing) in blood donor populations using multiple sensitive detection assays. METHODS: Several influenza RNA amplification assays, including transcription-mediated amplification (TMA) and 2 reverse-transcription polymerase chain reaction (RT-PCR) assays, were evaluated and used to test donor samples. Retrospective samples from 478 subjects drawn at sites with high influenza activity were tested. Prospective samples were collected from 1004 blood donors who called their donation center within 3 days of donation complaining of influenza-like illness (ILI). The plasma collected on the day of donation for these subjects was tested. RESULTS: Of the repository samples, 2 of 478 plasma samples were initially reactive but not repeat reactive by influenza TMA. Of blood donors reporting ILI symptoms postdonation, 1 of 1004 samples was TMA initially reactive but not repeat reactive; all samples were nonreactive by RT-PCR testing. CONCLUSIONS: Targeting blood donor populations most likely to have influenza infection, we failed to detect influenza RNA in 1482 donor samples, with most tested by 3 different RNA assays. Seasonal influenza does not appear to pose a significant contamination threat to the blood supply.

Insights from linking police domestic abuse data and health data in South Wales, UK: a linked routine data analysis using decision tree classification.

BACKGROUND: Exposure to domestic abuse can lead to long-term negative impacts on the victim's physical and psychological wellbeing. The 1998 Crime and Disorder Act requires agencies to collaborate on crime reduction strategies, including data sharing. Although data sharing is feasible for individuals, rarely are whole-agency data linked. This study aimed to examine the knowledge obtained by integrating information from police and health-care datasets through data linkage and analyse associated risk factor clusters. METHODS: This retrospective cohort study analyses data from residents of South Wales who were victims of domestic abuse resulting in a Public Protection Notification (PPN) submission between Aug 12, 2015 and March 31, 2020. The study links these data with the victims' health records, collated within the Secure Anonymised Information Linkage databank, to examine factors associated with the outcome of an Emergency Department attendance, emergency hospital admission, or death within 12 months of the PPN submission. To assess the time to outcome for domestic abuse victims after the index PPN submission, we used Kaplan-Meier survival analysis. We used multivariable Cox regression models to identify which factors contributed the highest risk of experiencing an outcome after the index PPN submission. Finally, we created decision trees to describe specific groups of individuals who are at risk of experiencing a domestic abuse incident and subsequent outcome. FINDINGS: After excluding individuals with multiple PPN records, duplicates, and records with a poor matching score or missing fields, the resulting clean dataset consisted of 8709 domestic abuse victims, of whom 6257 (71·8%) were female. Within a year of a domestic abuse incident, 3650 (41·9%) individuals had an outcome. Factors associated with experiencing an outcome within 12 months of the PPN included younger victim age (hazard ratio 1·183 [95% CI 1·053-1·329], p=0·0048), further PPN submissions after the initial referral (1·383 [1·295-1·476]; p<0·0001), injury at the scene (1·484 [1·368-1·609]; p<0·0001), assessed high risk (1·600 [1·444-1·773]; p<0·0001), referral to other agencies (1·518 [1·358-1·697]; p<0·0001), history of violence (1·229 [1·134-1·333]; p<0·0001), attempted strangulation (1·311 [1·148-1·497]; p<0·0001), and pregnancy (1·372 [1·142-1·648]; p=0·0007). Health-care data before the index PPN established that previous Emergency Department and hospital admissions, smoking, smoking cessation advice, obstetric codes, and prescription of antidepressants and antibiotics were associated with having a future outcome following a domestic abuse incident. INTERPRETATION: The results indicate that vulnerable individuals are detectable in multiple datasets before and after involvement of the police. Operationalising these findings could reduce police callouts and future Emergency Department or hospital admissions, and improve outcomes for those who are vulnerable. Strategies include querying previous Emergency Department and hospital admissions, giving a high-risk assessment for a pregnant victim, and facilitating data linkage to identify vulnerable individuals. FUNDING: National Institute for Health Research.

The Impact of Implementing a "Pain, Agitation, and Delirium Bundle" in a Pediatric Intensive Care Unit: Improved Delirium Diagnosis.

Delirium is associated with significant negative outcomes, yet it remains underdiagnosed in children. We describe the impact of implementing a pain, agitation, and delirium (PAD) bundle on the rate of delirium detection in a pediatric intensive care unit (PICU). This represents a single-center, pre-/post-intervention retrospective and prospective cohort study. The study was conducted at a PICU in a quaternary university-affiliated pediatric hospital. All patients consecutively admitted to the PICU in October and November 2017 and 2018. Purpose of the study was describe the impact of the implementation of a PAD bundle. The rate of delirium detection and the utilization of sedative and analgesics in the pre- and post-implementation phases were measured. A total of 176 and 138 patients were admitted during the pre- and post-implementation phases, respectively. Of them, 7 (4%) and 44 (31.9%) were diagnosed with delirium ( p < 0.001). Delirium was diagnosed in the first 48 hours of PICU admission and lasted for a median of 2 days (interquartile range [IQR]: 2-4). Delirium diagnosis was higher in patients receiving invasive ventilation ( p < 0.001). Compliance with the PAD bundle scoring was 79% for the delirium scale. Score results were discussed during medical rounds for 68% of the patients in the post-implementation period. The number of patients who received opioids and benzodiazepines and the cumulative doses were not statistically different between the two cohorts. More patients received dexmedetomidine and the cumulative daily dose was higher in the post-implementation period ( p < 0.001). The implementation of a PAD bundle in a PICU was associated with an increased recognition of delirium diagnosis. Further studies are needed to evaluate the impact of this increased diagnostic rate on short- and long-term outcomes.

Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells.

PURPOSE: To determine the anti-inflammatory and anti-oxidant effects of epigallocatechin gallate (EGCG), the major polyphenol component of green tea, in human corneal epithelial cells (HCEpiC). METHODS: HCEpiC were challenged with interleukin-1ß (IL-1ß) for 18 h or hyperosmolarity (440 mOsm) for 24 h. Luminex technology was used to determine the effects of EGCG (0.3-30 µM) on IL-1ß- or hyperosmolar-induced cytokine release into the medium. Cell metabolic activity was measured using the alamarBlue assay. Effects of EGCG on mitogen-activated protein kinase (MAPK) phosphorylation were determined by cell-based enzyme-linked immunosorbent assay (ELISA) and western blotting. Effects of EGCG on nuclear factor kappa B (NFκB) and activator protein-1 (AP-1) transcriptional activity were assessed by reporter gene assay. The effects of EGCG on glucose oxidase (GO)-induced reactive oxygen species (ROS) production was determined using the ROS probe CM-H2DCFDA. RESULTS: Treatment of HCEpiC with 1 ng/ml IL-1ß for 18 h significantly increased release of the cytokines/chemokines granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1), while hyperosmolarity-induced release of IL-6 and MCP-1. When cells were treated with IL-1ß and EGCG or hyperosmolarity and EGCG there was a dose-dependent reduction in release of these cytokines/chemokines, with significant inhibition observed at 3-30 µM. There was no effect of EGCG on cell metabolic activity at any of the doses tested (0.3-30 µM). EGCG significantly inhibited phosphorylation of the MAPKs p38 and c-Jun N-terminal kinase (JNK), and NFκB and AP-1 transcriptional activities. There was a significant dose-dependent decrease in GO-induced ROS levels after treatment of HCEpiC with EGCG. CONCLUSIONS: EGCG acts as an anti-inflammatory and anti-oxidant agent in HCEpiC and therefore may have therapeutic potential for ocular inflammatory conditions such as dry eye.

Comparison of two red-cell transfusion strategies after pediatric cardiac surgery: a subgroup analysis.

OBJECTIVE: To determine the impact of a restrictive vs. a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome in children post cardiac surgery. The optimal transfusion threshold after cardiac surgery in children is unknown. DESIGN: Randomized, controlled trial. SETTING: Tertiary pediatric intensive care units. PATIENTS: Participants are a subgroup of pediatric patients post cardiac surgery from the TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units) study. Exclusion criteria specific to the cardiac surgery subgroup included: age <28 days and patients remaining cyanotic. INTERVENTION: Critically ill children with a hemoglobin < or = 95 g/L within 7 days of pediatric intensive care unit admission were randomized to receive prestorage leukocyte-reduced red-cell transfusion if their hemoglobin dropped either <70 g/L (restrictive) or 95 g/L (liberal). MEASUREMENTS AND MAIN RESULTS: Postoperative cardiac patients (n = 125) from seven centers were enrolled. The restrictive (n = 63) and liberal (n = 62) groups were similar at baseline in age (mean +/- standard deviation = 31.4 +/- 38.1 mos vs. 26.4 +/- 39.1 mos), surgical procedure, severity of illness (Pediatric Risk of Mortality score = 3.4 +/- 3.2 vs. 3.2 +/- 3.2), multiple organ dysfunction syndrome (46% vs. 44%), mechanical ventilation (62% vs. 60%), and hemoglobin (83 vs. 80 g/L). Mean hemoglobin remained 21 g/L lower in the restrictive group after randomization. No significant difference was found in new or progressive multiple organ dysfunction syndrome (primary outcome) in the restrictive group vs. liberal group (12.7% vs. 6.5%; p = .36), pediatric intensive care unit length of stay (7.0 +/- 5.0 days vs. 7.4 +/- 6.4 days) or 28-day mortality (3.2% vs. 3.2%). CONCLUSION: In this subgroup analysis of cardiac surgery patients, a restrictive red-cell transfusion strategy, as compared with a liberal one, was not associated with any significant difference in new or progressive multiple organ dysfunction syndrome, but this evidence is not definitive.

Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells.

PURPOSE: Increasing evidence suggests that tear hyperosmolarity is a central mechanism causing ocular surface inflammation and damage in dry eye disease. Mapracorat (BOL-303242-X) is a novel glucocorticoid receptor agonist currently under clinical evaluation for use in the treatment of dry eye disease. This study assessed the anti-inflammatory effects of mapracorat in an in vitro osmotic stress model which mimics some of the pathophysiological changes seen in dry eye. METHODS: Human corneal epithelial cells were cultured in normal osmolar media (317 mOsM) or 440 mOsM hyperosmolar media for 24 h. Luminex technology was used to determine the effect of mapracorat on hyperosmolar-induced cytokine release. Effects of mapracorat on mitogen-activated protein kinase (MAPK) phosphorylation were determined by cell based ELISA. Effects of mapracorat on nuclear factor kappa B (NFkappaB) and activator protein-1 (AP-1) transcriptional activity were assessed by reporter gene assay. Dexamethasone was used as a control. RESULTS: Hyperosmolar conditions induced release of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) from cultured human corneal epithelial cells, and altered the phosphorylation state of p38 and c-Jun N-terminal kinase (JNK) and transcriptional activity of NFkappaB and AP-1. Incubation of cells with mapracorat inhibited hyperosmolar-induced cytokine release with comparable activity and potency as dexamethasone. This inhibition was reversed by the glucocorticoid receptor antagonist mifepristone (RU-486). Increased phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat. Mapracorat also significantly decreased the hyperosmolar-induced increase in NFkappaB and AP-1 transcriptional activity. CONCLUSIONS: Mapracorat acts as a potent anti-inflammatory agent in corneal epithelial cells challenged with osmotic stress, with comparable activity to the traditional steroid dexamethasone. These in vitro data suggest that mapracorat may be efficacious in the treatment of dry eye disease.

Impact of the site specialty of a continuity practice on students' clinical skills: performance with standardized patients.

BACKGROUND: The assessment of clinical competence and the impact of training in ambulatory settings are two issues of importance in the evaluation of medical student performance. PURPOSE: This study compares the clinical skills performance of students placed in three types of community preceptors' offices (pediatrics, medicine, family medicine) on yearly clinical skills assessments with standardized patients. Our goal was to see if the site specialty impacted on clinical performance. METHODS: The students in the study were completing a 3-year continuity preceptorship at a site representing one of the disciplines. Their performance on the four clinical skills assessments was compared. RESULTS: There was no significant difference in history taking, physical exam, communication, or clinical reasoning in any year (ANOVA p< or = .05) There was a small but significant difference in performance on a measure of interpersonal and interviewing skills during Years 1 and 2. CONCLUSION: The site specialty of an early clinical experience does not have a significant impact on performance of most of the skills measured by the assessments.