Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza.

Background: Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection. Methods: We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05). Results: Comparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week. Conclusion: Thus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.

Variability in IRBs regarding parental acceptance of passive consent.

OBJECTIVE: Passive, opt-out recruitment strategies have the potential to improve efficiency and enlarge the participant pool for clinical studies. We report on the feasibility of using a passive consent strategy for a multicenter pediatric study. METHODS: We assessed the response to passive and active control recruitment strategies used in a multicenter pediatric cohort study and describe the variability in acceptance among institutional review boards (IRBs) and parents of pediatric patients. RESULTS: Twenty-six pediatric centers submitted IRB applications; 24 centers participated. Sixteen IRBs approved the proposed passive recruitment strategy, and 6 IRBs required active consent strategies; 2 centers used a modified participation mode using control subjects from neighboring centers. In all, 4529 potential participants were identified across 22 centers. In the pre-enrollment phase, opt-out rates were significantly lower in the passive consent group compared with the active recruitment centers (1.6% vs. 11.8%; P < .001). During the enrollment phase, however, refusal rates in the passive consent group were significantly higher (38.1% vs. 12.2%; P = .004). The overall refusal rate across both groups was 33.3%. CONCLUSIONS: IRB variability in interpretation and application of regulations affects consistency of study procedure across sites and may reduce validity of study findings. Opt-out consent allowed us to create a large representative pool of control subjects. Parents were more likely to refuse to be approached for a study in the pre-enrollment phase when active consent was used, but were more likely to decline actual study enrollment when passive consent was used in the pre-enrollment period.

A case of abrin toxin poisoning, confirmed via quantitation of L-abrine (N-methyl-L-tryptophan) biomarker.

INTRODUCTION: The seeds of Abrus precatorius contain the highly toxic plant protein abrin. There is no antidote for abrin poisoning. Management, largely supportive, may consist of administering intravenous fluids, anti-emetics, and activated charcoal depending on the time of exposure. We report the presentation of a single case of unintentional abrin poisoning confirmed by the quantitation of L-abrine biomarker. CASE REPORT: A previously healthy 22-month-old, 11.5-kg female presented to the hospital after ingesting approximately 20 rosary peas (A. precatorius) sold as a "peace bracelet". Her primary manifestations were episodes of forceful emesis that included food particles progressing to clear gastric fluid. The patient was tachycardic (HR = 134 bpm) but had brisk capillary refill and normal blood pressure (96/60 mmHg). Laboratory testing revealed elevated blood urea nitrogen (16 mg/dL) and serum creatinine (0.4 mg/dL). In the emergency department, the patient was resuscitated with 40 mL/kg normal saline via peripheral IV and received ondansetron (0.15 mg/kg IV) to control retching. The patient was discharged well 24 h after the ingestion. DISCUSSION: This is the first case of human abrin toxin poisoning confirmed by the quantitation of L-abrine as a biomarker. Quantifying the levels of abrin toxin in the body after exposure can help clinicians make informed decisions when managing patients with symptomatic exposures to seeds of A. precatorius.

Ventilator-associated tracheobronchitis in a mixed medical/surgical pediatric ICU.

BACKGROUND: Adult studies have demonstrated that ventilator-associated tracheobronchitis (VAT) may be a precursor to ventilator-associated pneumonia (VAP). No published data on VAT in pediatric ICUs (PICUs) were found. The purposes of this retrospective, descriptive study are to describe the incidence, characteristics, and outcomes of patients at risk for VAT and formalize a process of VAT surveillance in the PICU population. METHODS: All patients meeting criteria for VAT during 2009-2010 were reviewed and data collected on risk of mortality, index of mortality, interventions, demographic data, respiratory cultures, and the organisms identified in culture. RESULTS: Of 645 patients (32.7%) admitted who met mechanical ventilation criteria, 22 (3.4%) met criteria for VAT. Patients with VAT experienced a significantly longer mean length of stay in the PICU (27.6±22.043 days vs 6.61±7.27 days; P=.000) and higher mean total ventilator time (519.31±457.60 h vs 95.60±138.83 h; P=.000). There was a significant association between tracheostomy and VAT (P=.000) and between chronic ventilator dependence and VAT (P=.002). Gram-negative rods accounted for 71% of cultured microorganisms; staphylococcal or streptococcal species were identified as 26% of causative pathogens. Six of 25 (24%) VAT events identified two or more potentially causative pathogens; four of these (67%) were in patients with a tracheostomy. CONCLUSIONS: VAT occurred less frequently in our PICU than reported in adult studies, and no cases of VAT progressed to VAP in our population. Our results suggest that VAT is a clinically significant health-care-associated infection in the PICU population.

Fluid balance in critically ill children with acute lung injury.

OBJECTIVES: In the Fluid and Catheter Treatment Trial (NCT00281268), adults with acute lung injury randomized to a conservative vs. liberal fluid management protocol had increased days alive and free of mechanical ventilator support (ventilator-free days). Recruiting sufficient children with acute lung injury into a pediatric trial is challenging. A Bayesian statistical approach relies on the adult trial for the a priori effect estimate, requiring fewer patients. Preparing for a Bayesian pediatric trial mirroring the Fluid and Catheter Treatment Trial, we aimed to: 1) identify an inverse association between fluid balance and ventilator-free days; and 2) determine if fluid balance over time is more similar to adults in the Fluid and Catheter Treatment Trial liberal or conservative arms. DESIGN: Multicentered retrospective cohort study. SETTING: Five pediatric intensive care units. PATIENTS: Mechanically ventilated children (age≥1 month to <18 yrs) with acute lung injury admitted in 2007-2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fluid intake, output, and net fluid balance were collected on days 1-7 in 168 children with acute lung injury (median age 3 yrs, median PaO2/FIO2 138) and weight-adjusted (mL/kg). Using multivariable linear regression to adjust for age, gender, race, admission day illness severity, PaO2/FIO2, and vasopressor use, increasing cumulative fluid balance (mL/kg) on day 3 was associated with fewer ventilator-free days (p=.02). Adjusted for weight, daily fluid balance on days 1-3 and cumulative fluid balance on days 1-7 were higher in these children compared to adults in the Fluid and Catheter Treatment Trial conservative arm (p<.001, each day) and was similar to adults in the liberal arm. CONCLUSIONS: Increasing fluid balance on day 3 in children with acute lung injury at these centers is independently associated with fewer ventilator-free days. Our findings and the similarity of fluid balance patterns in our cohort to adults in the Fluid and Catheter Treatment Trial liberal arm demonstrate the need to determine whether a conservative fluid management strategy improves clinical outcomes in children with acute lung injury and support a Bayesian trial mirroring the Fluid and Catheter Treatment Trial.

Incidence and risk factors associated with venous thrombotic events in pediatric intensive care unit patients.

OBJECTIVE: To evaluate the incidence and risk factors associated with venous thromboembolism (VTE) in children admitted to pediatric intensive care units (PICUs). DESIGN: Prospective observational study. SETTING: Eleven tertiary care PICUs in the United States. PATIENTS: Children who were admitted to PICUs and had radiographically confirmed VTE over a rolling 6-month period were enrolled in the study. Demographic, patient-related, and outcomes data were collected and compared with all children admitted during the same period. INTERVENTIONS: None. RESULTS: : Sixty-six symptomatic VTE were documented in sixty-two patients among 6653 patients admitted to 11 PICUs. Thirteen (19.7%) of the thrombi were present on admission. The incidence rate was 0.74% (range, 0-2.7% per PICU) with a point prevalence of 0.93%. Doppler ultrasound was most frequently used to diagnose or confirm a suspected VTE. Variables associated with unadjusted risk for VTE include: younger age (3.8 months for patients with VTE vs. 51 months for non-VTE patients, p < .001), cardiac diagnosis (41% in VTE cases vs. 15% in non-VTE, p < .001), pre-/post-operative status (63% in VTE cases vs. 40% in non-VTE, p = .001), presence of central venous catheter (88% in VTE case vs. 17% in non-VTE, p < .001), or mechanical ventilation (85% in VTE cases vs. 30% non-VTE, p < .001). Multivariate analysis showed increased risk of VTE with CVC (odds ratio 6.9; confidence interval 2.7-17.5) and mechanical ventilation (odds ratio 2.8; confidence interval 0.98-7.93). Children with VTE were sicker (Pediatric Index of Mortality 2 score risk of mortality of 3.0% vs. 0.9%; p<0.0001), stayed longer in the ICU (21.2 days vs. 1.6 days; p < .0001) and had increased mortality (10.2% vs. 2.6; p < .0001). CONCLUSIONS: Children admitted to the PICU have an increased risk of VTE. The presence of a CVC is the strongest risk factor for VTE in this PICU population. Children with VTE were younger, sicker, stayed longer in PICU, and had a higher mortality rate.

Current treatment practices of venous thromboembolism in children admitted to pediatric intensive care units.

OBJECTIVE: To describe current treatment practices of VTE in patients admitted to a pediatric intensive care unit (PICU) and compare these practices to published guidelines. BACKGROUND: While the incidence of VTE is increasing, current treatment practices of VTE in patients admitted to PICUs are not known. METHODS: This multicenter, prospective, observational study enrolled patients with confirmed VTE admitted to 11 PICUs over a rolling 6-month study period. Treatment data were collected and analyzed. RESULTS: Sixty-six VTEs occurred in 6653 patients. Empiric treatment for VTE was initiated in 30% prior to VTE confirmation, and children with cyanotic heart disease were 15.7 times more like to receive empiric therapy. Overall, 78% received systemic anticoagulation, 8% treated with only catheter-based interventions, and 13% of VTE were not treated. Seven patients (11%) underwent systemic fibrinolysis; more commonly in neonates (23%) vs children (5%). Surgical and interventional procedures were performed on 4 patients. The American College of Chest Physicians recommendations were incompletely followed. Only 28% of the 32 cases treated with low molecular weight heparin titrated dosing to a goal anti-FXa level 0.5-1. Five of the 15 cases treated with unfractionated heparin titrated dosing to aPTT 60-90, and one case did not use goal-directed therapy. CONCLUSIONS: Confirmed VTEs in patients admitted to PICUs are most frequently treated with systemic anticoagulation; however, more intensive treatments such as systemic thrombolysis and surgical or interventional procedures are not uncommon in this critically ill population. Current practices deviate from the published antithrombotic guidelines developed for the general pediatric population.

Mortality-adjusted duration of mechanical ventilation in critically ill children with symptomatic central venous line-related deep venous thrombosis.

OBJECTIVE: To determine the association between symptomatic central venous line-related deep venous thrombosis and a mortality-adjusted measure of duration of mechanical ventilation in critically ill children with central venous lines. DESIGN: Retrospective matched cohort study. SETTING: Eleven pediatric intensive care units across the United States. PATIENTS: Twenty-nine index critically ill children with central venous line-related deep vein thrombosis from a previous prospective observational study on symptomatic venous thromboembolism were compared with 116 control children with central venous lines without venous thrombosis. Each index patient was matched to four control patients based on age group, disease category, severity of illness score, and number of days in the intensive care unit before central venous line insertion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Index patients were appropriately matched to control patients with similar characteristics between the two groups. Index patients had fewer ventilator-free days (ie, days alive and breathing unassisted within 28 days after central venous line insertion) compared with matched control patients (16.8 ± 11.5 days vs. 22.3 ± 4.9 days, p = .040). Index patients also had less intensive care unit-free days (ie, days alive and discharged from the intensive care unit within 28 days after central venous line insertion) (9.8 ± 9.9 days vs. 17.9 ± 5.7 days, p < .001). Durations of mechanical ventilation (17.6 ± 40.6 days vs. 5.2 ± 5.5 days, p = .236) and intensive care unit stay (38.1 ± 61.7 days vs. 11.9 ± 10.9 days, p = .011) were longer in index patients. The mortality rate was statistically similar between the two groups. CONCLUSIONS: The presence of symptomatic central venous line-related deep vein thrombosis is associated with worse outcomes, particularly fewer ventilator-free days, in critically ill children. The causal relationship that deep venous thrombosis leads to impairment in lung function and delays weaning from mechanical ventilation and discharge from the intensive care unit needs to be proven prospectively. Ventilator-free days is a possible alternative outcome measure for future deep venous thrombosis studies.

Finding the right words: using the terms allow natural death (AND) and do not resuscitate (DNR) in pediatric palliative care.

When children are dying in a hospital setting, healthcare providers need to help families make important end-of-life care decisions. Most providers use the term do not resuscitate (DNR) when suggesting a course of action that involves not using extraordinary lifesaving measures. Some healthcare providers use the term allow natural death (AND) to discuss this same approach. This study investigated pediatric healthcare providers' beliefs about using AND as opposed to DNR. Results revealed that providers believe the term AND is somewhat ambiguous but may be more family centered.

Comfort and confidence levels of health care professionals providing pediatric palliative care in the intensive care unit.

Most childhood deaths that occur in the hospital happen in the pediatric intensive care unit. Providing pediatric palliative care in the intensive care unit comes with unique challenges due to the acute care, curative and often medically aggressive focus of these settings. In this study, 190 PICU health care professionals reported on their comfort and confidence in providing palliative care. Findings indicate that professionals report only a moderate level of comfort and confidence in this type of care in the pediatric ICU. For physicians and nurses, comfort and confidence was significantly higher for those who had practiced 8 years or more. Practitioners reported less comfort in providing psychosocial care. Implications for the social work role on the interdisciplinary team and suggestions for future research are discussed.