Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy.

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.

Airway microbiome dynamics and relationship to ventilator-associated infection in intubated pediatric patients.

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.

Evaluation of antibiotic treatment decisions in pediatric intensive care units in Saudi Arabia: A national survey.

OBJECTIVE: To describe variables used by Saudi pediatric intensivists to make antibiotic-related decisions for children with suspected severe bacterial infections. METHODS: We conducted a cross-sectional survey, which was developed using a multi-step methodological approach. The survey included 4 clinical scenarios of the most relevant bacterial infections in pediatric critical care (pneumonia, sepsis, meningitis and intra-abdominal infection). The potential determinants of antibiotic treatment duration addressed in all scenarios included clinical variables (patient characteristics, disease severity), laboratory infection markers, radiologic findings, and pathogens. RESULTS: The response rate was 65% (55/85). Eight variables (immunodeficiency, 3 months of age, 2 or more organ dysfunctions, Pediatric Risk of Mortality III score >10, leukocytosis, elevated C-reactive protein [CRP], elevated erythrocyte sedimentation rate [ESR], and elevated procalcitonin [PCT]) were associated with prolonging antibiotic treatment duration for all 4 clinical scenarios, with a median increase ranging from 3.0 days (95% confidence interval [CI] 0.5, 3.5, leukocytosis) to 8.8 days (95% CI 5.5, 10.5, immunodeficiency). There were no variables that were consistently associated with shortening antibiotic duration across all scenarios. Lastly, the proportion of physicians who would continue antibiotics for ≥5 days despite a positive viral polymerase chain reaction test result was 67% for pneumonia, 85% for sepsis, 63% for meningitis, and 95% for intra-abdominal infections. CONCLUSION: Antibiotic-related decisions for critically ill patients are complex and depend on several factors. Saudi pediatric intensivists will use prolonged courses of antibiotics for younger patients, patients with severe clinical picture, and patients with persistently elevated laboratory markers and hospital acquired infections, even when current literature and guidelines do not suggest such practices. Antimicrobial stewardship programs should include interventions to address these misconceptions to ensure the rational use of antibiotics in pediatric intensive care units.

Compliance With an Antibiotic Guideline for Suspected Ventilator-Associated Infection: The Ventilator-Associated INfection (VAIN2) Study.

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.

Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions.

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.

International Survey on Determinants of Antibiotic Duration and Discontinuation in Pediatric Critically Ill Patients.

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.

Development of Persistent Respiratory Morbidity in Previously Healthy Children After Acute Respiratory Failure.

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.

All in Your Mind? New-Onset Dysphagia in a Previously Healthy Adolescent Child.

A healthy 11-year-old male develops fear of choking secondary to progressive dysphagia that began in early childhood. No organic cause is found, and the patient is diagnosed with psychiatric oral aversion. The child is eventually transferred to a psychiatric facility, where a month later he has a possible aspiration event and is transferred to the local emergency room for respiratory distress before being admitted to the intensive care unit. Workup is notable for abnormal findings on brain imaging, and the diagnosis of Alexander's disease is made. This case highlights the importance of complete history-taking and examinations in pediatric patients.

Erratum: All in Your Mind? New-Onset Dysphagia in a Previously Healthy Adolescent Child.

[This corrects the article DOI: 10.1055/s-0039-3401008.].

Development of an Antibiotic Guideline for Children With Suspected Ventilator-Associated Infections.

OBJECTIVES: 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. DESIGN: Prospective, multicenter observational data collection and subsequent development of an antibiotic guideline. SETTING: Twenty-two PICUs. PATIENTS: Children less than 3 years old receiving mechanical ventilation who underwent clinical testing and initiation of antibiotics for suspected ventilator-associated infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 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 (p < 0.001) and higher PEdiatric Logistic Organ Dysfunction 2 scores (p < 0.001) 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. CONCLUSIONS: 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.

Paediatric acute respiratory distress syndrome incidence and epidemiology (PARDIE): an international, observational study.

BACKGROUND: Paediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS. METHODS: In this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death. FINDINGS: Between May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14-20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10-15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26-41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16-36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62-0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58-0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58-0·70; p=0·01). INTERPRETATION: The PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS. FUNDING: University of Southern California Clinical Translational Science Institute, Sainte Justine Children's Hospital, University of Montreal, Canada, Réseau en Santé Respiratoire du Fonds de Recherche Quebec-Santé, and Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine.

Estimating the probability of abusive head trauma after abuse evaluation.

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.

Pediatric Ventilator-Associated Events: Analysis of the Pediatric Ventilator-Associated Infection Data.

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.

Cognitive Development One Year After Infantile Critical Pertussis.

OBJECTIVES: 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. DESIGN: Prospective cohort study. SETTING: 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. PATIENTS: 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. INTERVENTIONS: The Mullen Scales of Early Learning was administered at a 1-year follow-up visit. Functional status was determined by examination and parental interview. MEASUREMENTS AND MAIN RESULTS: 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 (p < 0.001), 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 (p < 0.003) and Hispanic ethnicity (p < 0.008) were associated with lower mean Early Learning Composite score, but presenting symptoms and PICU course were not. CONCLUSIONS: Infants who survive critical pertussis often have neurodevelopmental deficits. These infants may benefit from routine neurodevelopmental screening.

Determinants of Antibiotic Tailoring in Pediatric Intensive Care: A National Survey.

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.

The intensive care medicine clinical research agenda in paediatrics.

BACKGROUND: 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. METHODS: 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? RESULTS: (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. CONCLUSION: 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.

Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial.

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.