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BACKGROUND: Little is known about the airway microbiome in intubated mechanically ventilated children. We sought to characterize the airway microbiome longitudinally and in association with clinical variables and possible ventilator-associated infection (VAI). METHODS: Serial tracheal aspirate samples were prospectively obtained from mechanically ventilated subjects under 3 years old from eight pediatric intensive care units in the United States from June 2017 to July 2018. Changes in the tracheal microbiome were analyzed by sequencing bacterial 16S ribosomal RNA gene relative to subject demographics, diagnoses, clinical parameters, outcomes, antibiotic treatment, and the Ventilator-Associated InfectioN (VAIN) score. RESULTS: A total of 221 samples from 58 patients were processed and 197 samples met the >1000 reads criteria (89%), with an average of 43,000 reads per sample. The median number of samples per subject was 3 (interquartile range [IQR]: 2–5), with a median VAIN score of 2 (IQR: 1–3). Proteobacteria was the highest observed phyla throughout the intubation period, followed by Firmicutes and Actinobacteria. Alpha diversity was negatively associated with days of intubation (p = .032) and VAIN score (p = .016). High VAIN scores were associated with a decrease of Mycobacterium obuense, and an increase of Streptococcus peroris, Porphyromonadaceae family (unclassified species), Veillonella atypica, and several other taxa. No specific pattern of microbiome composition related to clinically diagnosed VAIs was observed. CONCLUSIONS: Our data demonstrate decreasing alpha diversity with increasing VAIN score and days of intubation. No specific microbiome pattern was associated with clinically diagnosed VAI.

OBJECTIVES To evaluate a guideline for antibiotic decisions in children with suspected ventilator-associated infection. DESIGN Prospective, observational cohort study conducted in 22 PICUs in the United States and Canada. SETTING PICUs in 22 hospitals from April 2017 to January 2019. SUBJECTS Children less than 3 years old on mechanical ventilation greater than 48 hours who had respiratory secretions cultured and antibiotics initiated for suspected ventilator-associated infection. INTERVENTIONS After baseline data collection in children with suspected ventilator-associated infection (Phase 1), a consensus guideline was developed for advising antibiotic continuation or stopping at 48-72 hours (Phase 2) and implemented (Phase 3). Guideline-based antibiotic recommendations were provided to the treating clinicians once clinical and microbiologic data were available. Demographic and outcome data were collected, and guideline compliance and antibiotic utilization evaluated for Phase 1 and Phase 3. MEASUREMENTS AND MAIN RESULTS Despite education and implementation efforts, guideline-concordant antibiotic management occurred in 158 of 227 (70%) Phase 3 subjects compared with 213 of 281 (76%) in Phase 1. Illness severity and positive respiratory cultures were the primary determinants of antibiotic continuation. For subjects with a positive respiratory culture but a score for which antibiotic discontinuation was recommended (score ≤ 2), only 27% of Phase 3 subjects had antibiotics discontinued. Antibiotic continuation was not associated with improved outcomes in these subjects and was associated with significantly longer duration of ventilation (median 5.5 d longer) and PICU stay (5 d longer) in the overall study population. Positive respiratory cultures were not associated with outcomes irrespective of antibiotic treatment. CONCLUSIONS Antibiotic guideline efficacy and safety remain uncertain due to clinician failure to follow the guideline, instead primarily relying on respiratory culture results. Strategies to overcome clinician perceptions of respiratory cultures and other barriers will be vital for improving guideline adherence and antibiotic use in suspected ventilator-associated infection in future studies.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Objectives Acute respiratory failure is a common reason for admission to PICUs. Short- and long-term effects on pulmonary health in previously healthy children after acute respiratory failure requiring mechanical ventilation are unknown. The aim was to determine if clinical course or characteristics of mechanical ventilation predict persistent respiratory morbidity at follow-up. Design Prospective cohort study with follow-up questionnaires at 6 and 12 months. Setting Ten U.S. PICUs. Patients Two-hundred fifty-five children were included in analysis after exclusion for underlying chronic disease or incomplete data. One-hundred fifty-eight and 130 children had follow-up data at 6 and 12 months, respectively. Interventions None. Measurements and main results Pulmonary dysfunction at discharge a priori defined as one of: mechanical ventilation, supplemental oxygen, bronchodilators or steroids at 28 days or discharge. Persistent respiratory morbidity a priori defined as a respiratory PedsQL, a pediatric quality of life measure, greater than or equal to 5 or asthma diagnosis, bronchodilator or inhaled steroids, or unscheduled clinical evaluation for respiratory symptoms. Multivariate backward stepwise regression using Akaike information criterion minimization determined independent predictors of these outcomes. Pulmonary dysfunction at discharge was present in 34% of patients. Positive bacterial respiratory culture predicted pulmonary dysfunction at discharge (odds ratio, 4.38; 95% CI, 1.66-11.56). At 6- and 12-month follow-up 42% and 44% of responders, respectively, had persistent respiratory morbidity. Pulmonary dysfunction at discharge was associated with persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months was strongly predictive of 12-month persistent respiratory morbidity (odds ratio, 18.58; 95% CI, 6.68-52.67). Positive bacterial respiratory culture remained predictive of persistent respiratory morbidity in patients at both follow-up points. Conclusions Persistent respiratory morbidity develops in up to potentially 44% of previously healthy children less than or equal to 24 months old at follow-up after acute respiratory failure requiring mechanical ventilation. This is the first study, to our knowledge, to suggest a prevalence of persistent respiratory morbidity and the association between positive bacterial respiratory culture and pulmonary morbidity in a population of only previously healthy children with acute respiratory failure.

Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

To develop a guideline for the decision to continue or stop antibiotics at 48-72 hours after their initiation in children with suspected ventilator-associated infection.Prospective, multicenter observational data collection and subsequent development of an antibiotic guideline.Twenty-two PICUs.Children less than 3 years old receiving mechanical ventilation who underwent clinical testing and initiation of antibiotics for suspected ventilator-associated infection.None.Phase 1 was a prospective data collection in 281 invasively ventilated children with suspected ventilator-associated infection. The median age was 8 months (interquartile range, 4-16 mo) and 75% had at least one comorbidity. Phase 2 was development of the guideline scoring system by an expert panel employing consensus conferences, literature search, discussions with institutional colleagues, and refinement using phase 1 data. Guideline scores were then applied retrospectively to the phase 1 data. Higher scores correlated with duration of antibiotics (p0.001) and higher PEdiatric Logistic Organ Dysfunction 2 scores (p0.001) but not mortality, PICU-free days or ventilator-free days. Considering safety and outcomes based on the phase 1 data and aiming for a 25% reduction in antibiotic use, the panel recommended stopping antibiotics at 48-72 hours for guideline scores less than or equal to 2, continuing antibiotics for scores greater than or equal to 6, and offered no recommendation for scores 3, 4, and 5. The acceptability and effect of these recommendations on antibiotic use and outcomes will be prospectively tested in phase 3 of the study.We developed a scoring system with recommendations to guide the decision to stop or continue antibiotics at 48-72 hours in children with suspected ventilator-associated infection. The safety and efficacy of the recommendations will be prospectively tested in the planned phase 3 of the study.

Background Evidence-based, patient-specific estimates of abusive head trauma probability can inform physicians’ decisions to evaluate, confirm, exclude, and/or report suspected child abuse. Objective To derive a clinical prediction rule for pediatric abusive head trauma that incorporates the (positive or negative) predictive contributions of patients’ completed skeletal surveys and retinal exams. Participants and Setting 500 acutely head-injured children under three years of age hospitalized for intensive care at one of 18 sites between 2010 and 2013. Methods Secondary analysis of an existing, cross-sectional, prospective dataset, including (1) multivariable logistic regression to impute the results of abuse evaluations never ordered or completed, (2) regularized logistic regression to derive a novel clinical prediction rule that incorporates the results of completed abuse evaluations, and (3) application of the new prediction rule to calculate patient-specific estimates of abusive head trauma probability for observed combinations of its predictor variables. Results Applying a mean probability threshold of >0.5 to classify patients as abused, the 7-variable clinical prediction rule derived in this study demonstrated sensitivity 0.73 (95% CI: 0.66-0.79) and specificity 0.87 (95% CI: 0.82-0.90). The area under the receiver operating characteristics curve was 0.88 (95% CI: 0.85-0.92). Patient-specific estimates of abusive head trauma probability for 72 observed combinations of its seven predictor variables ranged from 0.04 (95% CI: 0.02-0.08) to 0.98 (95% CI: 0.96-0.99). Conclusions Seven variables facilitate patient-specific estimation of abusive head trauma probability after abuse evaluation in intensive care settings.

Objectives We hypothesized that antibiotic use in PICUs is based on criteria not always supported by evidence. We aimed to describe determinants of empiric antibiotic use in PICUs in eight different countries. Design Cross-sectional survey. Setting PICUs in Canada, the United States, France, Italy, Saudi Arabia, Japan, Thailand, and Brazil. Subjects Pediatric intensivists. Interventions None. Measurements and main results We used literature review and focus groups to develop the survey and its clinical scenarios (pneumonia, septic shock, meningitis, and intra-abdominal infections) in which cultures were unreliable due to antibiotic pretreatment. Data analyses included descriptive statistics and linear regression with bootstrapped SEs. Overall response rate was 39% (482/1,251), with individual country response rates ranging from 25% to 76%. Respondents in all countries prolonged antibiotic duration based on patient characteristics, disease severity, pathogens, and radiologic findings (from a median increase of 1.8 d [95% CI, 0.5-4.0 d] to 9.5 d [95% CI, 8.5-10.5 d]). Younger age, severe disease, and ventilator-associated pneumonia prolonged antibiotic treatment duration despite a lack of evidence for such practices. No variables were reported to shorten treatment duration for all countries. Importantly, more than 39% of respondents would use greater than or equal to 7 days of antibiotics for patients with a positive viral polymerase chain reaction test in all scenarios, except in France for pneumonia (29%), septic shock (13%), and meningitis (6%). The use of elevated levels of inflammatory markers to prolong antibiotic treatment duration varied among different countries. Conclusions Antibiotic-related decisions are complex and may be influenced by cultural and contextual factors. Evidence-based criteria are necessary to guide antibiotic duration and ensure the rational use of antibiotics in PICUs.

OBJECTIVES To describe the criteria that currently guide empiric antibiotic treatment in children admitted to Canadian PICUs. DESIGN Cross-sectional survey. SETTING Canadian PICUs. SUBJECTS Pediatric intensivists and pediatric infectious diseases specialists. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We used focus groups and literature review to design the survey questions and its four clinical scenarios (sepsis, pneumonia, meningitis, and intra-abdominal infections). We analyzed our results using descriptive statistics and multivariate linear regression. Our response rate was 60% for pediatric intensivists (62/103) and 36% for pediatric infectious diseases specialists (37/103). Variables related to patient characteristics, disease severity, pathogens, and clinical, laboratory, and radiologic infection markers were associated with longer courses of antibiotics, with median increment ranging from 1.75 to 7.75 days. The presence of positive viral polymerase chain reaction result was the only variable constantly associated with a reduction in antibiotic use (median decrease from, -3.25 to -8.25 d). Importantly, 67-92% of respondents would still use a full course of antibiotics despite positive viral polymerase chain reaction result and marked clinical improvement for patients with suspected sepsis, pneumonia, and intra-abdominal infection. Clinical experience was associated with shorter courses of antibiotics for meningitis and sepsis (-1.3 d [95% CI, -2.4 to -0.2] and -1.8 d [95% CI, -2.8 to -0.7] per 10 extra years of clinical experience, respectively). Finally, site and specialty also influenced antibiotic practices. CONCLUSIONS Decisions about antibiotic management for PICU patients are complex and involve the assessment of several different variables. With the exception of a positive viral polymerase chain reaction, our findings suggest that physicians rarely consider reducing the duration of antibiotics despite clinical improvement. In contrast, they will prolong the duration when faced with a nonreassuring characteristic. The development of objective and evidence-based criteria to guide antibiotic therapy in critically ill children is crucial to ensure the rational use of these agents in PICUs.

Intensive Care Medicine set us the task of outlining a global clinical research agenda for paediatric intensive care (PIC). In line with the clinical focus of this journal, we have limited this to research that may directly influence patient care. Clinician researchers from PIC research networks of varying degrees of formality from around the world were invited to answer two main questions: (1) What have been the major recent advances in paediatric critical care research? (2) What are the top 10 studies for the next 10 years? (1) Inclusive databases are well established in many countries. These registries allow detailed observational studies and feasibility testing of clinical trial protocols. Recent trials are larger and more valuable, and (2) most common interventions in PIC are not evidenced-based. Clinical studies for the next 10 years should address this deficit, including: ventilation techniques and interfaces; fluid, transfusion and feeding strategies; optimal targets for vital signs; multiple organ failure definitions, mechanisms and treatments; trauma, prevention and treatment; improving safety; comfort of the patient and their family; appropriate care in the face of medical complexity; defining post-PICU outcomes; and improving knowledge generation and adoption, with novel trial design and implementation strategies. The group specifically highlighted the need for research in resource-limited environments wherein mortality remains often tenfold higher than in well-resourced settings. Paediatric intensive care research has never been healthier, but many gaps in knowledge remain. We need to close these urgently. The impact of new knowledge will be greatest in resource-limited environments.

Objectives: To determine the frequency of low-tidal volume ventilation in pediatric acute respiratory distress syndrome and assess if any demographic or clinical factors improve low-tidal volume ventilation adherence. Design: Descriptive post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies. Setting: Twenty-six academic PICU. Patients: Three hundred fifteen pediatric acute respiratory distress syndrome patients. Measurements and Main Results: All patients who received conventional mechanical ventilation at hours 0 and 24 of pediatric acute respiratory distress syndrome who had data to calculate ideal body weight were included. Two cutoff points for low-tidal volume ventilation were assessed: less than or equal to 6.5 mL/kg of ideal body weight and less than or equal to 8 mL/kg of ideal body weight. Of 555 patients, we excluded 240 for other respiratory support modes or missing data. The remaining 315 patients had a median PaO2-to-FIO2 ratio of 140 (interquartile range, 90–201), and there were no differences in demographics between those who did and did not receive low-tidal volume ventilation. With tidal volume cutoff of less than or equal to 6.5 mL/kg of ideal body weight, the adherence rate was 32% at hour 0 and 33% at hour 24. A low-tidal volume ventilation cutoff of tidal volume less than or equal to 8 mL/kg of ideal body weight resulted in an adherence rate of 58% at hour 0 and 60% at hour 24. Low-tidal volume ventilation use was no different by severity of pediatric acute respiratory distress syndrome nor did adherence improve over time. At hour 0, overweight children were less likely to receive low-tidal volume ventilation less than or equal to 6.5 mL/kg ideal body weight (11% overweight vs 38% nonoverweight; p = 0.02); no difference was noted by hour 24. Furthermore, in the overweight group, using admission weight instead of ideal body weight resulted in misclassification of up to 14% of patients as receiving low-tidal volume ventilation when they actually were not. Conclusions: Low-tidal volume ventilation is underused in the first 24 hours of pediatric acute respiratory distress syndrome. Age, Pediatric Risk of Mortality-III, and pediatric acute respiratory distress syndrome severity were not associated with improved low-tidal volume ventilation adherence nor did adherence improve over time. Overweight children were less likely to receive low-tidal volume ventilation strategies in the first day of illness.

The pediatric Critical Illness Stress-induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis.Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category.There were 134 immune-competent children without lymphopenia, 79 previously immune-competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis ( P.05) and on the rate of nosocomial infection and sepsis per 100 patient days ( P.05). Whey protein treatment protected immune-competent patients without lymphopenia from infection and sepsis, both nutraceutical strategies were equivalent in immune-competent patients with lymphopenia, and zinc, selenium, glutamine, and metoclopramide treatment protected immunocompromised patients from infection and sepsis.The science of immune nutrition is more complex than previously thought. Future trial design should consider immune status at the time of trial entry because differential effects of nutraceuticals may be related to this patient characteristic.

Objective To replicate the previously published finding that the absence of a history of trauma in a child with obvious traumatic head injuries demonstrates high specificity and high positive predictive value (PPV) for abusive head trauma. Study design This was a secondary analysis of a deidentified, cross-sectional dataset containing prospective data on 346 young children with acute head injury hospitalized for intensive care across 18 sites between 2010 and 2013, to estimate the diagnostic relevance of a caregiver's specific denial of any trauma, changing history of accidental trauma, or history of accidental trauma inconsistent with the child's gross motor skills. Cases were categorized as definite or not definite abusive head trauma based solely on patients' clinical and radiologic findings. For each presumptive historical “red flag,” we calculated sensitivity, specificity, predictive values, and likelihood ratio (LR) with 95% CI for definite abusive head trauma in all patients and also in cohorts with normal, abnormal, or persistent abnormal neurologic status. Results A caregiver's specific denial of any trauma demonstrated a specificity of 0.90 (95% CI, 0.84-0.94), PPV of 0.81 (95% CI, 0.71-0.88), and a positive LR (LR+) of 4.83 (95% CI, 3.07-7.61) for definite abusive head trauma in all patients. Specificity and LR+ were lowest—not highest—in patients with persistent neurologic abnormalities. The 2 other historical red flags showed similar trends. Conclusions A caregiver's specific denial of any trauma, changing history of accidental trauma, or history of accidental trauma that is developmentally inconsistent are each highly specific (>0.90) but may provide weaker support than previously reported for a diagnosis of abusive head trauma in patients with persistent neurologic abnormalities.

Objectives To compare the prevalence of infection applying the proposed pediatric ventilator-associated events criteria versus clinician-diagnosed ventilator-associated infection to subjects in the pediatric ventilator-associated infection study. Design Analysis of prospectively collected data from the pediatric ventilator-associated infection study. Setting PICUs of 47 hospitals in the United States, Canada, and Australia. Patients Two-hundred twenty-nine children ventilated for greater than 48 hours who had respiratory secretion cultures performed to evaluate for suspected ventilator-associated infection. Interventions None. Measurements and main results Applying the proposed pediatric ventilator-associated event criteria, 15 of 229 subjects in the ventilator-associated infection study qualified as "ventilator-associated condition" and five of 229 (2%) met criteria for "infection-related ventilator-associated complication." This was compared with 89 of 229 (39%) diagnosed as clinical ventilator-associated infection (Kappa = 0.068). Ten of 15 subjects identified as ventilator-associated condition did not meet criteria for infection-related ventilator-associated complication primarily because they did not receive 4 days of antibiotics. Ventilator-associated condition subjects were similar demographically to nonventilator-associated condition subjects and had similar mortality (13% vs 10%), PICU-free days (6.9 ± 7.7; interquartile range, 0-14 vs 9.8 ± 9.6; interquartile range, 0-19; p = 0.25), but fewer ventilator-free days (6.6 ± 9.3; interquartile range, 1-15 vs 12.4 ± 10.7; interquartile range, 0-22; p = 0.04). The clinical ventilator-associated infection diagnosis in the ventilator-associated infection study was associated with fewer PICU-free days but no difference in mortality or ventilator-free days. Conclusions The ventilator-associated event criteria appear to be insensitive to the clinical diagnosis of ventilator-associated infection. Differentiation between ventilator-associated condition and infection-related ventilator-associated complication was primarily determined by the clinician decision to treat with antibiotics rather than clinical signs and symptoms. The utility of the proposed pediatric ventilator-associated event criteria as a surrogate for ventilator-associated infection criteria is unclear.

Pertussis can cause life-threatening illness in infants. Data regarding neurodevelopment after pertussis remain scant. The aim of this study was to assess cognitive development of infants with critical pertussis 1 year after PICU discharge.Prospective cohort study.Eight hospitals comprising the Eunice Kennedy Shriver National Institute for Child Health and Human Development Collaborative Pediatric Critical Care Research Network and 18 additional sites across the United States.Eligible patients had laboratory confirmation of pertussis infection, were less than 1 year old, and were admitted to the PICU for at least 24 hours.The Mullen Scales of Early Learning was administered at a 1-year follow-up visit. Functional status was determined by examination and parental interview.Of 196 eligible patients, 111 (57%) completed the Mullen Scales of Early Learning. The mean scores for visual reception, receptive language, and expressive language domains were significantly lower than the norms (p0.001), but not fine and gross motor domains. Forty-one patients (37%) had abnormal scores in at least one domain and 10 (9%) had an Early Learning Composite score 2 or more SDs below the population norms. Older age (p0.003) and Hispanic ethnicity (p0.008) were associated with lower mean Early Learning Composite score, but presenting symptoms and PICU course were not.Infants who survive critical pertussis often have neurodevelopmental deficits. These infants may benefit from routine neurodevelopmental screening.

OBJECTIVE: We sought to compare the performance of the 2008 CDC pediatric criteria for ventilator-associated pneumonia (VAP), the 2013 adult ventilator associated condition (VAC) criteria, the new Draft pediatric VAC criteria, and physician-diagnosed VAP in a cohort of pediatric intensive care unit (PICU) patients. DESIGN: Secondary analysis of a previously conducted prospective observational study. SETTING: PICU within a tertiary care children’s hospital between April 1, 2010 and April 1, 2011. PATIENTS: Patients between 31 days and 18 years of age, mechanically ventilated via endotracheal tube for more than 72 hours and no limitations of care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VAP criteria applied in real time and VAC criteria applied retrospectively. Outcomes assessed between cases and non-cases within criteria. Of the 133 eligible participants, 24 (18%) had VAP by 2008 Pediatric criteria, and 27 (20%) by physician diagnosis. Sixteen (12%) and 10 (8%) had VAC by 2013 Adult and Draft Pediatric criteria, respectively. We found significant overlap between cases identified with 2008 Pediatric criteria and Physician diagnosis (p=0.549), but comparisons between the other definitions revealed that the newer criteria identify different patients than previous CDC VAP criteria and Physician diagnosis (p

BACKGROUND Surfactant has been shown to be dysfunctional in ARDS, and exogenous surfactant has proven effective in many forms of neonatal and pediatric acute lung injury (ALI). In view of the positive results of our studies in children along with evidence that surfactant-associated protein B containing pharmaceutical surfactants might be more effective, we designed a multiinstitutional, randomized, controlled, and masked trial of calfactant, a calf lung surfactant, in adults and children with ALI/ARDS due to direct lung injury. METHODS Adult subjects within 48 h of initiation of mechanical ventilation for direct ARDS were randomized to receive up to three interventions with instilled calfactant vs air placebo. The primary outcome was 90-day all-cause mortality. RESULTS Three hundred seventeen subjects were enrolled, 308 of whom could be evaluated. There were no significant baseline differences between groups. Calfactant administration was not associated with improved survival, lengths of stay, or oxygenation. Calfactant instillation was frequently associated with transient hypoxia and hypotension. The study was stopped at the first interim analysis at the sponsor's request. CONCLUSIONS Administration of calfactant was not associated with improved oxygenation or longer-term benefits relative to placebo in this randomized, controlled, and masked trial. At present, exogenous surfactant cannot be recommended for routine clinical use in ARDS. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00682500; URL: www.clinicaltrials.gov.

Background Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza severity in adults. IFITM3 has not been evaluated in pediatric influenza. Methods The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA. Results In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the Δ21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified. Conclusions rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.

Objectives:The cortisol response during critical illness varies widely among patients. Our objective was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the c

BACKGROUND: In recent years, the focus on patient safety and housestaff supervision has led to a steady increase in institutions providing 24/7 in-hospital (also known as in-house, henceforth referred to as IH) coverage by pediatric intensivists. Effects of this increased attending physician presence on education of pediatric housestaff have not been studied. We hypothesized that IH coverage would decrease perceived autonomy of housestaff and negatively affect their preparedness to be independent attending physicians on completion of training. METHODS: A secure, anonymous, Web-based survey was sent to pediatric intensivists in the United States and Canada, and pediatric critical care fellows and pediatric residents at academic centers across the United States. Questions focused on perceptions of IH coverage and housestaff educational experience. RESULTS: We report 1323 responses from 147 institutions (center response rate 74%). Although 96% of respondents stated that the PICU provides “a good educational experience,” only 50% of pediatric intensivists and 67% of housestaff feel that housestaff are prepared for independent practice after training in an IH model. Compared with those training in home-call models, respondents currently working in IH models have more favorable perceptions of the effects of IH coverage on housestaff autonomy (P < .0001), supervision (P < .0001), and preparation for independent practice (P < .0001). CONCLUSIONS: Pediatric intensivists and housestaff express concern regarding the preparation of housestaff training in a 24/7 IH attending model. An important priority for institutions using or considering a 24/7 IH attending coverage model is the balance between adequate housestaff supervision and autonomy.

Objectives: Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials. Design: Case study, narrative review. Methods: The Data and Safety Monitoring Board’s role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described. Findings: The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility. Conclusions: The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups. (Pediatr Crit Care Med 2013; 14:374–383)

The provision of nutritional supplements with the ability to affect cells of the immune system is a promising therapy that may help to maintain immune system efficacy and prevent infection (1). Three natural immunomodulators important for lymphocyte health are zinc, selenium, and prolactin. The multicenter Critical Illness Stress Induced Immune Suppression (CRISIS) Prevention Trial evaluated the effect of zinc, selenium, glutamine, and metoclopramide (a prolactin secretagogue) vs. whey supplementation on the development of infection and sepsis in critically ill children (2). As part of the trial, baseline serum levels of zinc, selenium, and prolactin were obtained within 72 hours of PICU admission. In this report, we describe these baseline values and their relationships to lymphocyte counts. We hypothesized that zinc, selenium, and prolactin concentrations are low in critically ill children early after PICU admission and that low concentrations are associated with lymphopenia.

OBJECTIVE To describe the planned aims and methodology of the Pediatric Acute Lung Injury Consensus Conference. DESIGN Consensus conference of experts in pediatric acute lung injury. METHODS A panel of 26 experts in pediatric acute lung injury will meet over the course of one year to develop a better taxonomy to define pediatric acute lung injury, specifically predisposing factors, etiology, and pathophysiology. A modified Delphi approach that emphasizes strong professional agreement will be utilized. RESULTS The Pediatric Acute Lung Injury Consensus Conference will aim for consensus development on the following topics related to pediatric acute lung injury: 1) definition, incidence, and epidemiology; 2) comorbidities and severity; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive support and ventilation; 8) extracorporeal support; and 9) morbidity and long-term outcomes. CONCLUSIONS The importance of this effort for improving care and guiding future research in pediatric acute lung injury is clear. Despite the many epidemiologic, interventional, and outcome studies undertaken by pediatric intensivists worldwide, our understanding of this disease process is limited, and morbidity and mortality remain unacceptably high. By consolidating the knowledge and expertise of the leaders of the field of pediatric acute lung injury, we hope to develop a framework for future progress.

OBJECTIVES:: Abusive head trauma is a leading cause of traumatic death and disability during infancy and early childhood. Evidence-based screening tools for abusive head trauma do not exist. Our research objectives were 1) to measure the predictive relationships between abusive head trauma and isolated, discriminating, and reliable clinical variables and 2) to derive a reliable, sensitive, abusive head trauma clinical prediction rule that-if validated-can inform pediatric intensivists' early decisions to launch (or forego) an evaluation for abuse. DESIGN:: Prospective, multicenter, cross-sectional, observational. SETTING:: Fourteen PICUs. PATIENTS:: Acutely head-injured children less than 3 years old admitted for intensive care. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Applying a priori definitional criteria for abusive head trauma, we identified clinical variables that were discriminating and reliable, calculated likelihood ratios and post-test probabilities of abuse, and applied recursive partitioning to derive an abusive head trauma clinical prediction rule with maximum sensitivity-to help rule out abusive head trauma, if negative. Pretest probability (prevalence) of abusive head trauma in our study population was 0.45 (95 of 209). Post-test probabilities of abusive head trauma for isolated, discriminating, and reliable clinical variables ranged from 0.1 to 0.86. Some of these variables, when positive, shifted probability of abuse upward greatly but changed it little when negative. Other variables, when negative, largely excluded abusive head trauma but increased probability of abuse only slightly when positive. Some discriminating variables demonstrated poor inter-rater reliability. A cluster of five discriminating and reliable variables available at or near the time of hospital admission identified 97% of study patients meeting a priori definitional criteria for abusive head trauma. Negative predictive value was 91%. CONCLUSIONS:: A more complete understanding of the specific predictive qualities of isolated, discriminating, and reliable variables could improve screening accuracy. If validated, a reliable, sensitive, abusive head trauma clinical prediction rule could be used by pediatric intensivists to calculate an evidence-based, patient-specific estimate of abuse probability that can inform-not dictate-their early decisions to launch (or forego) an evaluation for abuse. Language: en

To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit.Prospective, observational study with 100% accrual of eligible patients.Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network.Four hundred nineteen children treated with morphine or fentanyl infusions.None.Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03).Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

Suspected ventilator-associated infection is the most common reason for antibiotics in the PICU. We sought to characterize the clinical variables associated with continuing antibiotics after initial evaluation for suspected ventilator-associated infection and to determine whether clinical variables or antibiotic treatment influenced outcomes.Prospective, observational cohort study conducted in 47 PICUs in the United States, Canada, and Australia. Two hundred twenty-nine pediatric patients ventilated more than 48 hours undergoing respiratory secretion cultures were enrolled as "suspected ventilator-associated infection" in a prospective cohort study, those receiving antibiotics of less than or equal to 3 days were categorized as "evaluation only," and greater than 3 days as "treated." Demographics, diagnoses, comorbidities, culture results, and clinical data were compared between evaluation only and treated subjects and between subjects with positive versus negative cultures.PICUs in 47 hospitals in the United States, Canada, and Australia.All patients undergoing respiratory secretion cultures during the 6 study periods.None.Treated subjects differed from evaluation-only subjects only in frequency of positive cultures (79% vs 36%; p0.0001). Subjects with positive cultures were more likely to have chronic lung disease, tracheostomy, and shorter PICU stay, but there were no differences in ventilator days or mortality. Outcomes were similar in subjects with positive or negative cultures irrespective of antibiotic treatment. Immunocompromise and higher Pediatric Logistic Organ Dysfunction scores were the only variables associated with mortality in the overall population, but treated subjects with endotracheal tubes had significantly lower mortality.Positive respiratory cultures were the primary determinant of continued antibiotic treatment in children with suspected ventilator-associated infection. Positive cultures were not associated with worse outcomes irrespective of antibiotic treatment although the lower mortality in treated subjects with endotracheal tubes is notable. The necessity of continuing antibiotics for a positive respiratory culture in suspected ventilator-associated infection requires further study.

ObjectivesTo determine whether weight extremes impact clinical outcomes in pediatric acute respiratory distress syndrome.DesignPost hoc analysis of a cohort created by combining five multicenter pediatric acute respiratory distress syndrome studies.SettingForty-three academic PICUs worldwide.PatientsA total of 711 subjects prospectively diagnosed with pediatric acute respiratory distress syndrome.InterventionSubjects more than 2 years were included and categorized by Center for Disease Control and Prevention body mass index z score criteria: underweight (< -1.89), normal weight (-1.89 to +1.04), overweight (+1.05 to +1.64), and obese (≥ +1.65). Subjects were stratified by direct versus indirect lung injury leading to pediatric acute respiratory distress syndrome. The primary outcome was in-hospital mortality. In survivors, secondary analyses included duration of mechanical ventilation and ICU length of stay.Measurements and main resultsA total of 331 patients met inclusion criteria; 12% were underweight, 50% normal weight, 11% overweight, and 27% obese. Overall mortality was 20%. By multivariate analysis, body mass index category was independently associated with mortality (p = 0.004). When stratified by lung injury type, there was no mortality difference between body mass index groups with direct lung injury; however, in the indirect lung injury group, the odds of mortality in the obese were significantly lower than normal weight subjects (odds ratio, 0.11; 95% CI, 0.02-0.84). Survivors with direct lung injury had no difference in the duration of mechanical ventilation or ICU length of stay; however, those with indirect lung injury, the overweight required longer duration of mechanical ventilation than other groups (p < 0.001).ConclusionsThese data support the obesity paradox in pediatric acute respiratory distress syndrome. Obese children with indirect lung injury pediatric acute respiratory distress syndrome have a lower risk of mortality. Importantly, among survivors, the overweight with indirect lung injury requires longer duration of mechanical ventilation. Our data require prospective validation to further elucidate the pathobiology of this phenomenon.

BACKGROUND: Organ dysfunction scores, based on physiological parameters, have been created to describe organ failure. In a general pediatric intensive care unit (PICU) population, the PEdiatric Logistic Organ Dysfunction-2 score (PELOD-2) score had both a good discrimination and calibration, allowing to describe the clinical outcome of critically ill children throughout their stay. This score is increasingly used in clinical trials in specific subpopulation. Our objective was to assess the performance of the PELOD-2 score in a subpopulation of critically ill children requiring plasma transfusions.METHODS: This was an ancillary study of a prospective observational study on plasma transfusions over a 6-week period, in 101 PICUs in 21 countries. All critically ill children who received at least one plasma transfusion during the observation period were included. PELOD-2 scores were measured on days 1, 2, 5, 8, and 12 after plasma transfusion. Performance of the score was assessed by the determination of the discrimination (area under the ROC curve: AUC) and the calibration (Hosmer-Lemeshow test).RESULTS: Four hundred and forty-three patients were enrolled in the study (median age and weight: 1 year and 9.1 kg, respectively). Observed mortality rate was 26.9 % (119/443). For PELOD-2 on day 1, the AUC was 0.76 (95 % CI 0.71-0.81) and the Hosmer-Lemeshow test was p = 0.76. The serial evaluation of the changes in the daily PELOD-2 scores from day 1 demonstrated a significant association with death, adjusted for the PELOD-2 score on day 1.CONCLUSIONS: In a subpopulation of critically ill children requiring plasma transfusion, the PELOD-2 score has a lower but acceptable discrimination than in an entire population. This score should therefore be used cautiously in this specific subpopulation.

Objectives: The Critical Illness Stress-Induced Immune Suppression prevention trial was a randomized, masked trial of zinc, selenium, glutamine, and metoclopramide compared with whey protein in delaying nosocomial infection in PICU patients. One fourth of study subjects were diagnosed with nosocomial lower respiratory infection, which contributed to subjects receiving antibiotics 74% of all patient days in the PICU. We analyzed diagnostic and treatment variability among the participating institutions and compared outcomes between nosocomial lower respiratory infection subjects (n = 74) and intubated subjects without nosocomial infection (n = 1 55). Design: Post hoc analysis. Setting: Eight hospitals in the Collaborative Pediatric Critical Care Research Network. Patients: Critical Illness Stress-Induced Immune Suppression study subjects. Interventions: None. Measurements and Main Results: Variability across institutions existed in the frequency and manner by which respiratory secretion cultures were obtained, processed, and results reported. Most results were reported semiquantitatively, and both Gram stains and antibiotic sensitivities were frequently omitted. The nosocomial lower respiratory infection diagnosis was associated with increased PICU lengths of stay compared with those who were intubated without nosocomial infection (24 ± 19 vs 9 ± 6 d; p < 0.001) and antibiotic use (38 ± 29 vs 15 ± 20 antibiotics days; p < 0.001). Despite antibiotic treatment, the same bacteria persisted in 45% of follow-up cultures. Conclusions: The Critical Illness Stress-Induced Immune Suppression data demonstrate that the nosocomial lower respiratory infection diagnosis is associated with longer lengths of stay and increased antibiotic use, but there is considerable diagnostic and treatment variability across institutions. More rigorous standards for when and how respiratory cultures are obtained, processed, and reported are necessary. Bacterial persistence also complicates the interpretation of follow-up cultures. (Pediatr Crit Care Med 2016; XX:00–00)

Objective: Given pulse oximetry is increasingly substituting for arterial blood gas monitoring, noninvasive surrogate markers for lung disease severity are needed to stratify pediatric risk. We sought to validate prospectively the comparability of SpO 2 /Fio 2 to PaO 2 /Fio 2 and oxygen saturation index to oxygenation index in chil dren. We also sought to derive a noninvasive lung injury score. Design: Prospective, multicentered observational study in six pediatric intensive care units. Patients: One hundred thirty-seven mechanically ventilated chil dren with SpO 2 80% to 97% and an indwelling arterial catheter. Interventions: Simultaneous blood gas, pulse oximetry, and ventilator settings were collected. derivation and validation data sets were generated, and linear mixed modeling was used to de rive predictive equations. Model performance and fit were evaluated using the validation data set. Measurements and Main Results: One thousand one hundred ninety blood gas, SpO 2 , and ventilator settings from 137 patients were included. Oxygen saturation index had a strong linear association with oxygenation index in both derivation and validation data sets, given by the equation oxygen saturation index 5 2.76 1 0.547*oxygenation index (derivation). 1/SpO 2 /Fio 2 had a strong linear association with 1/PaO 2 /Fio 2 in both derivation and validation data sets given by the equation 1/SpO 2 /Fio 2 5 0.00232 1 0.443/PaO 2 /Fio 2 (derivation). SpO 2 / Fio 2 criteria for acute respiratory distress syndrome and acute lung injury were 221 (95% confidence interval 215–226) and 264 (95% confidence interval 259–269). Multivariate models demonstrated that oxygenation index, serum pH, and Pa co 2 were associated with oxygen saturation index (p < .05); and 1/PaO 2 /Fio 2 , mean airway pressure, serum pH, and Paco 2 were associated with 1/SpO 2 /Fio 2 (p < .05). There was strong concordance between the derived noninvasive lung injury score and the original pediatric modification of lung injury score with a mean difference of 20.0361 0.264 sd . Conclusions: Lung injury severity markers, which use SpO 2 , are adequate surrogate markers for those that use PaO 2 in children with respiratory failure for SpO 2 between 80% and 97%. They should be used in clinical practice to characterize risk, to increase enrollment in clinical trials, and to determine disease prevalence. (Crit Care Med 2012; 40:1309–1316)

Objectives: Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population. Design: Randomized, double-blinded, comparative effectiveness trial. Setting: Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Patients: Two hundred ninety-three long-term intensive care patients (age 1–17 yrs) expected to require >72 hrs of invasive care. Interventions: Patients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n 149), or daily enteral whey protein (n 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat. Measurements and Main Results: There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/ 100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p .011). Conclusion: Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient. (Pediatr Crit Care Med 2012; 13:165–173)

Objectives: Ascertainment of adrenal function assessing free rather that total cortisol may be beneficial for the diagnosis of critical illness-related cortisol insufficiency. We hypothesized that centrifugal ultrafiltration would provide timely free cortisol data that highly correlated with the gold standard, but logistically cumbersome, equilibrium dialysis technique when the free cortisol fractions were identically quantified by chemiluminescence immunoassay. We also hypothesized that free cortisol would correlate with illness severity in a large cohort of critically ill children. Design: Prospective, multi-institutional, observational cohort investigation. Setting: Seven pediatric intensive care units within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Patients: One hundred sixty-five critically ill children across the spectrum of illness severity. Interventions: Blood sampling. Measurements and Main Results: Time to derive plasma free cortisol concentrations after centrifugal ultrafiltration or equilibrium dialysis fractionation with chemiluminescence immunoassay was approximately 2 vs. approximately 24 hrs, respectively. Using centrifugal ultrafiltration, mean plasma free cortisol was 4.1 6.7 g/dL (median, 1.6 g/dL; range, 0.2‐43.6 g/L), representing an average of 15.2 9.4% of total cortisol. Nearly 60% of subjects exhibited free cortisol

Since the identification of surfactant deficiency as the putative cause of the infant respiratory distress syndrome (RDS) by Avery and Mead in 1959, our understanding of the role of pulmonary surfactant in respiratory physiology and the pathophysiology of acute lung injury (ALI) has advanced substantially. Surfactant replacement has become routine for the prevention and treatment of infant RDS and other causes of neonatal lung injury. The role of surfactant in lung injury beyond the neonatal period, however, has proven more complex. Relative surfactant deficiency, dysfunction, and inhibition all contribute to the disturbed physiology seen in ALI and acute respiratory distress syndrome (ARDS). Consequently, exogenous surfactant, while a plausible therapy, has proven to be less effective in ALI/ARDS than in RDS, where simple deficiency is causative. This failure may relate to a number of factors, among them inadequacy of pharmaceutical surfactants, insufficient dosing or drug delivery, poor drug distribution, or simply an inability of the drug to substantially impact the underlying pathophysiology of ALI/ARDS. Both animal and human studies suggest that direct types of ALI (eg, aspiration, pneumonia) may be more responsive to surfactant therapy than indirect lung injury (eg, sepsis, pancreatitis). Animal studies are needed, however, to further clarify aspects of drug composition, timing, delivery, and dosing before additional human trials are pursued, as the results of human trials to date have been inconsistent and largely disappointing. Further study and perhaps the development of more robust pharmaceutical surfactants offer promise that exogenous surfactant will find a place in our armamentarium of treatment of ALI/ARDS in the future.

This article examines exogenous lung surfactant replacement therapy and its utility in mitigating clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Biophysical research has documented that lung surfactant dysfunction can be reversed or mitigated by increasing surfactant concentration, and multiple studies in animals with ALI/ARDS have shown that respiratory function and pulmonary mechanics in vivo can be improved by exogenous surfactant administration. Exogenous surfactant therapy is a routine intervention in neonatal intensive care, and is life-saving in preventing or treating the neonatal respiratory distress syndrome (NRDS) in premature infants. In applications relevant for lung injury-related respiratory failure and ALI/ARDS, surfactant therapy has been shown to be beneficial in term infants with pneumonia and meconium aspiration lung injury, and in children up to age 21 with direct pulmonary forms of ALI/ARDS. However, extension of exogenous surfactant therapy to adults with respiratory failure and clinical ALI/ARDS remains a challenge. Coverage here reviews clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS, particularly focusing on its potential advantages in patients with direct pulmonary forms of these syndromes. Also discussed is the rationale for mechanism-based therapies utilizing exogenous surfactant in combination with agents targeting other aspects of the multifaceted pathophysiology of inflammatory lung injury. Additional factors affecting the efficacy of exogenous surfactant therapy in ALI/ARDS are also described, including the difficulty of effectively delivering surfactants to injured lungs and the existence of activity differences between clinical surfactant drugs.

To provide an updated overview of critical pertussis to the pediatric critical care community and describe a study of critical pertussis recently undertaken.The six sites, seven hospitals of the Collaborative Pediatric Critical Care Research Network, and 17 outside sites at academic medical centers with pediatric intensive care units.Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in US children, especially among infants. In pediatric intensive care units, Bordetella pertussis is a community-acquired pathogen associated with critical illness and death. The incidence of medical and developmental sequelae in critical pertussis survivors remains unknown, and the appropriate strategies for treatment and support remain unclear. The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study has begun to evaluate critical pertussis in a prospective cohort.Research is urgently needed to provide an evidence base that might optimize management for critical pertussis, a serious, disabling, and too often fatal illness for U.S. children and those in the developing world.

OBJECTIVE To investigate critical care physicians' experiences and perspectives regarding follow-up meetings with parents after a child's death in the pediatric intensive care unit. Parents of children who die in the pediatric intensive care unit often desire a follow-up meeting with the physicians who cared for their child. DESIGN Semistructured, audio-recorded telephone interviews. SETTING Six clinical centers affiliated with the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PARTICIPANTS Seventy critical care physicians (i.e., attendings and fellows) practicing or training at a Child Health and Human Development Collaborative Pediatric Critical Care Research Network clinical center between February 1, 2008 and June 30, 2008. MEASUREMENTS AND MAIN RESULTS Twenty-three (33%) physicians reported never participating in a follow-up meeting with bereaved parents; 22 (31%) participated in one to five meetings; and 25 (36%) participated in more than five meetings. Of those with prior experience, 44 (94%) met with parents at the hospital and 40 (85%) met within 3 months of the death. Meeting content included discussing autopsy, parent questions, hospital course, cause of death, genetic risk, bereavement services, and legal or administrative issues; providing emotional support; and receiving parent feedback. Forty (85%) physicians perceived the meetings to be beneficial to families, and 35 (74%) to physicians. Barriers included time and scheduling, family and physician unwillingness, distance and transportation, language and cultural issues, parent anger, and lack of a system for meeting initiation and planning. CONCLUSIONS Critical care physicians have a wide range of experience conducting follow-up meetings with bereaved parents. Although physicians perceive benefits to follow-up meetings, barriers exist that interfere with their implementation in clinical practice.

To assess the impact of calfactant (a modified natural bovine lung surfactant) in immunocompromised children with acute lung injury and to determine the number of patients required for a definitive clinical trial of calfactant in this population.Post hoc analysis of data from a previous randomized, control trial.Tertiary care pediatric intensive care units.All children, defined as immunocompromised, enrolled in a multicenter, masked, randomized, control trial of calfactant for acute lung injury conducted between July 2000 and July 2003.Patients received either an intratracheal instillation of calfactant or an equal volume of air placebo in a protocolized manner.Eleven of 22 (50%) calfactant-treated patients died when compared with 18 of 30 (60%) placebo patients (absolute risk reduction 10.0%, 95% confidence interval [CI] -17.3, 37.3). Among the 23 patients with an initial oxygen index (OI)/=13 and/=37, 44% (4 of 9) of calfactant-treated patients died in comparison with 71% (10 of 14) of placebo (absolute risk reduction 27.0%, 95% CI -13.2, 67.2). Only 33% (3 of 9) of calfactant patients died before intensive care discharge in comparison with 71% (10 of 14) of placebo (absolute risk reduction 38.1%, 95% CI -0.7, 76.9). Calfactant therapy was associated with improved oxygenation in these 23 patients. Using an OI entry criterion of (13/= OI/= 37), stratifying on the presence of hematopoietic stem cell transplantation, and accepting the 27% difference in mortality observed in this analysis, 63 patients would be required in each arm of a randomized, control trial to demonstrate a significant effect of calfactant on mortality in this patient population assuming a two-sided alpha of 0.05 and a power of 0.85.These preliminary data suggest a potential benefit of calfactant in this high-risk population. A clinical trial powered to appropriately assess these findings seems warranted and feasible.

This article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is on reviewing clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS, including the multifaceted pathology of inflammatory lung injury, the effectiveness of surfactant delivery in injured lungs, and composition-based activity differences among clinical exogenous surfactant preparations.

Objectives We document clinicians' stated blood glucose control practice patterns in North American pediatric and adult ICUs. Methods Using a Web-based self-administered questionnaire, we conducted a nationwide survey of North American pediatric and adult ICUs. Participants included ICU medical directors, nurses, fellows in training, and attending intensivists from participating ICUs in three critical care research networks. Measurements and main results Item generation and item selection were performed according to standard scientific survey methods. Questions were designed to describe clinicians' perceptions about glucose control practices. The questionnaire topics included the following: respondent characteristics; ICU description; hyperglycemia; hypoglycemia; and glucose measurement. The institutional response rate was 96% (50 of 52 institutions). The clinician response rate was 58% (163 of 282 physicians). Adult ICU clinicians defined hyperglycemia (120 mg/dL [6.2 mmol/L]) at a lower threshold than pediatric ICU clinicians (150 mg/dL [8.3 mmol/L]). Hypoglycemia was defined similarly by both groups (median, ≤60 mg/dL [3.3 mmol/L]; range, 40 to 80 mg/dL [2.2 to 4.4 mmol/L]). More pediatric ICU clinicians (84.5%) than adult ICU clinicians (59.1%) considered hypoglycemia to be more dangerous than hyperglycemia. A larger percentage of adult ICU clinicians (82.5%) than pediatric ICU clinicians (49.3%) preferred a target blood glucose level between 80 and 110 mg/dL (4.4 to 6.1 mmol/L). Clinical algorithms for glucose management varied among clinicians and across institutions. Conclusions Blood glucose control with insulin is used frequently for critically ill adults and children. A wide variation in practice exists in blood glucose targets, hyperglycemia and hypoglycemia definitions, and decision algorithms among North American adult and pediatric ICUs.

Study Objective. To determine the safety, effectiveness, and dosing of dexmedetomidine in intensive care infants and children who require sedation, and the rationale for patient selection. Design. Prospective observational study. Setting. Eleven-bed pediatric intensive care unit in a university-affiliated children's hospital. Patients. Seventeen infants and children who received dexmedetomidine consecutively between May 4, 2005, and May 4, 2006. Measurements and Main Results. Data were collected on demographics, blood pressure and heart rate measurements, and adverse effects. The rationale for dexmedetomidine use, its dosing, use of other sedatives, and treatment duration were also recorded. Twenty treatment courses in 17 patients (median age 5 mo, range 1 mo-17 yrs) were evaluated. Ten patients (59%) had chronic neurologic impairments (including Down syndrome in nine [53%]). Thirteen (76%) had undergone cardiac surgery, two (12%) had respiratory failure, one (6%) had endocarditis, and one (6%) had undergone scoliosis repair. In 15 (75%) of 20 cases, dexmedetomidine was started to minimize the use of midazolam before extubation; in 13 (87%) of these cases, the patients were extubated within 24 hours. The remaining patients could not tolerate midazolam, and dexmedetomidine was used as an alternative. No loading doses were given. The mean ± SD starting dose was 0.2 ± 0.2 μg/kg/hour, with a maximum of 0.5 ± 0.2 μg/kg/hour. Mean ± SD duration was 32 ± 21 hours (range 3–75 hrs); 10 courses exceeded 24 hours. Mean arterial pressures before and after starting treatment were not significantly different (p=0.76), nor were values at discontinuation (p=0.31) or 12 hours later (p=0.29). No significant differences were noted in heart rate at the start (p=0.09), at discontinuation (p=0.06), or 12 hours later (p=0.17). One patient (6%) developed hypotension; no other adverse effects were noted. Conclusion. With careful patient selection and a conservative approach to dosing, dexmedetomidine was a useful sedative in children requiring mechanical ventilation. It allowed for a reduction or elimination of other sedatives, and it was particularly useful in children with chronic neurologic impairments. Dexmedetomidine was well tolerated, with no clinically significant effects on blood pressure or heart rate.

Excellence in clinical care coupled with basic and applied research reflects the maturation of a medical subspecialty, advances that field, and provides objective data for identifying best practices. PICUs are uniquely suited for conducting translational and clinical research. In addition, multiple investigations have reported that a majority of parents are interested in their children's participation in clinical research, even when the research offers no direct benefit to their child. However, such activity may generate ethical conflict with bedside care providers trying to acutely identify the best approach for an individual critically ill child. Ultimately, this conflict may diminish enthusiasm for the generation of scientific evidence that supports the application of evidence-based medicine into PICU clinical standard work. Accordingly this review endeavors to provide an overview of current state PICU clinical research strengths, liabilities, opportunities, and barriers and contrast this with an established pediatric hematology-oncology iterative research model that constitutes a learning healthcare system.Narrative review of medical literature published in English.Currently, most PICU therapy is not evidence based. Developing a learning healthcare system in the PICU integrates clinical research into usual practice and fosters a culture of evidence-based learning and continual care improvement. As PICU mortality has significantly decreased, identification and validation of patient-centered, clinically relevant research outcome measures other than mortality is essential for future clinical trial design. Because most pediatric critical illness may be classified as rare diseases, participation in research networks will facilitate iterative, collaborative, multiinstitutional investigations that over time identify the best practices to improve PICU outcomes. Despite real ethical challenges, critically ill children and their families should have the opportunity to participate in translational/clinical research whenever feasible.

Drug delivery by aerosol may have several advantages over other modes, particularly if the lung is the target organ. Aerosol delivery may allow achievement of higher concentrations while minimizing systemic effects and offers convenience, rapid onset of action, and avoidance of the needles and sterile technique necessary with intravenous drug administration. Aerosol delivery may change the pharmacokinetics of many drugs, however, and an awareness of the caveats of aerosolized drug delivery is mandatory to ensure both safety and adequate drug delivery. This paper discusses the administration of surfactants, anti-inflammatory agents, and analgesics by the aerosol route.

Objective: To describe the final recommendations of the Pediatric Acute Lung Injury Consensus Conference.Design: Consensus conference of experts in pediatric acute lung injury.Setting: Not applicable.Subjects: PICU patients with evidence of acute lung injury or acute respiratory distress syndrome.Interventions: None.Methods: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published, data were lacking a modified Delphi approach emphasizing strong professional agreement was used.Measurements and Main Results: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published data were lacking a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the following topics related to pediatric acute respiratory distress syndrome: 1) Definition, prevalence, and epidemiology; 2) Pathophysiology, comorbidities, and severity; 3) Ventilatory support; 4) Pulmonary-specific ancillary treatment; 5) Nonpulmonary treatment; 6) Monitoring; 7) Noninvasive support and ventilation; 8) Extracorporeal support; and 9) Morbidity and long-term outcomes. There were 132 recommendations with strong agreement and 19 recommendations with weak agreement. Once restated, the final iteration of the recommendations had none with equipoise or disagreement.Conclusions: The Consensus Conference developed pediatric-specific definitions for acute respiratory distress syndrome and recommendations regarding treatment and future research priorities. These are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.