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The Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network originated over 20 years ago to foster research to optimize the care of critically ill infants and children. Over this period, PALISI has seen two major evolutions: formalization of our network infrastructure and a broadening of our clinical research focus. First, the network is unique in that its activities and meetings are funded by subscriptions from members who now comprise a multidisciplinary group of investigators from over 90 PICUs all over the United States (US) and Canada, with collaborations across the globe. In 2020, the network converted into a standalone, nonprofit organizational structure (501c3), making the PALISI Network formally independent of academic and clinical institutions or professional societies. Such an approach allows us to invest in infrastructure and future initiatives with broader opportunities for fund raising. Second, our research investigations have expanded beyond the original focus on sepsis and acute lung injury, to incorporate the whole field of pediatric critical care, for example, efficient liberation from mechanical ventilator support, prudent use of blood products, improved safety of intubation practices, optimal sedation practices and glucose control, and pandemic research on influenza and COVID-19. Our network approach in each field follows, where necessary, the full spectrum of clinical and translational research, including: immunobiology studies for understanding basic pathologic mechanisms; surveys to explore contemporary clinical practice; consensus conferences to establish agreement about literature evidence; observational prevalence and incidence studies to measure scale of a clinical issue or question; case control studies as preliminary best evidence for design of definitive prospective studies; and, randomized controlled trials for informing clinical care. As a research network, PALISI and its related subgroups have published over 350 peer-reviewed publications from 2002 through September 2022.

Infants younger than 6 months of age are at high risk for complications of coronavirus disease 2019 (Covid-19) and are not eligible for vaccination. Transplacental transfer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after maternal Covid-19 vaccination may confer protection against Covid-19 in infants.We used a case-control test-negative design to assess the effectiveness of maternal vaccination during pregnancy against hospitalization for Covid-19 among infants younger than 6 months of age. Between July 1, 2021, and March 8, 2022, we enrolled infants hospitalized for Covid-19 (case infants) and infants hospitalized without Covid-19 (control infants) at 30 hospitals in 22 states. We estimated vaccine effectiveness by comparing the odds of full maternal vaccination (two doses of mRNA vaccine) among case infants and control infants during circulation of the B.1.617.2 (delta) variant (July 1, 2021, to December 18, 2021) and the B.1.1.259 (omicron) variant (December 19, 2021, to March 8, 2022).A total of 537 case infants (181 of whom had been admitted to a hospital during the delta period and 356 during the omicron period; median age, 2 months) and 512 control infants were enrolled and included in the analyses; 16% of the case infants and 29% of the control infants had been born to mothers who had been fully vaccinated against Covid-19 during pregnancy. Among the case infants, 113 (21%) received intensive care (64 [12%] received mechanical ventilation or vasoactive infusions). Two case infants died from Covid-19; neither infant's mother had been vaccinated during pregnancy. The effectiveness of maternal vaccination against hospitalization for Covid-19 among infants was 52% (95% confidence interval [CI], 33 to 65) overall, 80% (95% CI, 60 to 90) during the delta period, and 38% (95% CI, 8 to 58) during the omicron period. Effectiveness was 69% (95% CI, 50 to 80) when maternal vaccination occurred after 20 weeks of pregnancy and 38% (95% CI, 3 to 60) during the first 20 weeks of pregnancy.Maternal vaccination with two doses of mRNA vaccine was associated with a reduced risk of hospitalization for Covid-19, including for critical illness, among infants younger than 6 months of age. (Funded by the Centers for Disease Control and Prevention.).

Spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, which led to increased U.S. hospitalizations for coronavirus disease 2019 (Covid-19), generated concern about immune evasion and the duration of protection from vaccines in children and adolescents.Using a case-control, test-negative design, we assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2 messenger RNA vaccine) at least 14 days before illness among case patients and controls, according to time since vaccination for patients 12 to 18 years of age and in periods coinciding with circulation of B.1.617.2 (delta) (July 1, 2021, to December 18, 2021) and omicron (December 19, 2021, to February 17, 2022) among patients 5 to 11 and 12 to 18 years of age.We enrolled 1185 case patients (1043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1627 controls. During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, -25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days).BNT162b2 vaccination reduced the risk of omicron-associated hospitalization by two thirds among children 5 to 11 years of age. Although two doses provided lower protection against omicron-associated hospitalization than against delta-associated hospitalization among adolescents 12 to 18 years of age, vaccination prevented critical illness caused by either variant. (Funded by the Centers for Disease Control and Prevention.).

The increasing incidence of pediatric hospitalizations associated with coronavirus disease 2019 (Covid-19) caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States has offered an opportunity to assess the real-world effectiveness of the BNT162b2 messenger RNA vaccine in adolescents between 12 and 18 years of age.We used a case-control, test-negative design to assess vaccine effectiveness against Covid-19 resulting in hospitalization, admission to an intensive care unit (ICU), the use of life-supporting interventions (mechanical ventilation, vasopressors, and extracorporeal membrane oxygenation), or death. Between July 1 and October 25, 2021, we screened admission logs for eligible case patients with laboratory-confirmed Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2) in case patients as compared with two hospital-based control groups: patients who had Covid-19-like symptoms but negative results on testing for SARS-CoV-2 (test-negative) and patients who did not have Covid-19-like symptoms (syndrome-negative).A total of 445 case patients and 777 controls were enrolled. Overall, 17 case patients (4%) and 282 controls (36%) had been fully vaccinated. Of the case patients, 180 (40%) were admitted to the ICU, and 127 (29%) required life support; only 2 patients in the ICU had been fully vaccinated. The overall effectiveness of the BNT162b2 vaccine against hospitalization for Covid-19 was 94% (95% confidence interval [CI], 90 to 96); the effectiveness was 95% (95% CI, 91 to 97) among test-negative controls and 94% (95% CI, 89 to 96) among syndrome-negative controls. The effectiveness was 98% against ICU admission and 98% against Covid-19 resulting in the receipt of life support. All 7 deaths occurred in patients who were unvaccinated.Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19-related hospitalization and ICU admission or the receipt of life support. (Funded by the Centers for Disease Control and Prevention.).

COVID-19 vaccination is recommended for persons who are pregnant, breastfeeding, trying to get pregnant now, or who might become pregnant in the future, to protect them from COVID-19.

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.

It remains unknown if pediatric patients failing initial noninvasive ventilation (NIV) experience worse clinical outcomes than those successfully treated with NIV or those primarily intubated.This was a single-center, retrospective review of patients admitted with acute respiratory failure to the University of Michigan pediatric intensive care or cardiothoracic ICUs and receiving NIV or invasive mechanical ventilation as first-line therapy.One hundred seventy subjects met inclusion criteria and were enrolled: 65 NIV success, 55 NIV failure, and 50 invasive mechanical ventilation alone. Of those failing NIV, median time to intubation was 1.8 (interquartile range [IQR]1-7) h. On multivariable regression, ICU-free days were significantly different between groups (NIV success: 22.9 ± 6.9 d; NIV failure: 13.0We demonstrated that critically ill pediatric subjects unsuccessfully trialed on NIV did not experience increased ICU length of stay or fewer ventilator-free days when compared to those on invasive mechanical ventilation alone, including in the pediatric ARDS subgroup. Our findings are predicated on a median time to intubation of2 h in the NIV failure group and the provision of adequate monitoring while on NIV.

Rationale: Racial disparities in pain management have been previously reported for children receiving emergency care. Objectives: To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure. Methods: Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white, n = 1,233), non-Hispanic Black (Black, n = 502), or Hispanic of any race (Hispanic, n = 536). Results: Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%). Conclusions: Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out. Clinical trial registered with clinicaltrials.gov (NCT 00814099).

Aims and objectives Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission. Methods Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested. Results Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05). Conclusions Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.

Objectives Common data elements are a combination of a precisely defined question paired with a specified set of responses. Common data elements contribute to the National Institutes of Health-supported principle of Findable, Accessible, Interoperable, and Reusableness of research data. Routine use of Common data elements and standardized definitions within pediatric critical care research are likely to promote collaboration, improve quality, and consistency of data collection, improve overall efficiency of study or trial setup, and facilitate cross-study comparisons, meta-analysis, and merging of study cohorts. The purpose of this Pediatric Critical Care Medicine Perspective is to establish a road map for the development of multinational, multidisciplinary consensus-based common data elements that could be adapted for use within any pediatric critical care subject area. Methods We describe a multistep process for the creation of "core domains" of research (e.g. patient outcomes, health-related conditions, or aspects of health) and the development of common data elements within each core domain. We define a tiered approach to data collection based on relevance of each common data element to future studies and clinical practice within the field of interest. Additionally, we describe the use of the Delphi methods to achieve consensus of these common data element documents using an international, multidisciplinary panel of experts.

Rationale: Few data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS).Objectives: To describe contemporary use of adjunctive therapies for early PARDS as a framework for future investigations.Methods: This was a preplanned substudy of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks.Measurements and Main Results: We investigated six adjunctive therapies for PARDS: continuous neuromuscular blockade, corticosteroids, inhaled nitric oxide (iNO), prone positioning, high-frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation. Almost half (45%) of children with PARDS received at least one therapy. Variability was noted in the median starting oxygenation index of each therapy; corticosteroids started at the lowest oxygenation index (13.0; interquartile range, 7.6-22.0) and HFOV at the highest (25.7; interquartile range, 16.7-37.3). Continuous neuromuscular blockade was the most common, used in 31%, followed by iNO (13%), corticosteroids (10%), prone positioning (10%), HFOV (9%), and extracorporeal membrane oxygenation (3%). Steroids, iNO, and HFOV were associated with comorbidities. Prone positioning and HFOV were more common in middle-income countries and less frequently used in North America. The use of multiple ancillary therapies increased over the first 3 days of PARDS, but there was not an easily identifiable pattern of combination or order of use.Conclusions: The contemporary description of prevalence, combinations of therapies, and oxygenation threshold for which the therapies are applied is important for design of future studies. Region of the world, income, and comorbidities influence adjunctive therapy use and are important variables to include in PARDS investigations.

Supplemental Digital Content is available in the text., Objectives: Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome. Design: Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children’s Hospital of Philadelphia. Setting: The derivation cohort represented 100 centers worldwide; the validation cohort was from Children’s Hospital of Philadelphia. Patients: There were 624 and 640 subjects in the derivation and validation cohorts, respectively. Interventions: None. Measurements and Main Results: The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and Pao2/Fio2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts. Conclusions: We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

Background Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). Methods Plasma was collected from inpatients ( Results Specificities of N and S assays were 95–97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28–3844 pg/mL (N) and 1.65–1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. Conclusions Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference.DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017).SETTING: Thirty-seven international PICUs.PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:FIO2 ratio, progressive tachycardia, and early diuretic administration.CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

OBJECTIVES To determine the presence, central characteristics, and impact on major morbidity and mortality of trauma-related pediatric acute respiratory distress syndrome. DESIGN Retrospective review of a prospective trauma database. SETTING American College of Surgeons verified level 1 trauma center in an urban setting. PATIENTS Trauma patients age 0 to 18 years old inclusive. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of the 7,382 patients presenting within the 10-year study period, 646 met study criteria for inclusion in the analysis. Trauma-related pediatric acute respiratory distress syndrome was present in 9% of the analyzed cohort. On univariate analysis and compared with those without, trauma-related pediatric acute respiratory distress syndrome occurred more commonly among those with traumatic brain injury (77.2% vs 45.5%; p < 0.001), non-accidental trauma (28.8% vs 10.2%; p < 0.001), and an injury severity score greater than 30 (27.1% vs 3.8%; p 0.001). New or progressive multiple organ dysfunction syndrome was significantly higher in trauma-related pediatric acute respiratory distress syndrome patients (86.7% vs 10.4%; p < 0.001) as was mortality (18.3% vs 3.1%; p < 0.001) than in those without. The presence of trauma-related pediatric acute respiratory distress syndrome (odds ratio, 6.98; 95% CI, 2.95-16.5; p < 0.001), younger age (odds ratio, 0.93; 95% CI, 0.87-0.99; p = 0.038), and worse injury severity (odds ratio, 1.19; 95% CI, 1.14-1.24; p < 0.001) were all independent statistical predictors of new or progressive multiple organ dysfunction syndrome in this retrospective cohort. Mortality in patients without trauma-related pediatric acute respiratory distress syndrome increased with increasing injury severity, whereas mortality in patients with trauma-related pediatric acute respiratory distress syndrome was the same regardless of injury severity. On multivariable regression analysis, while age and injury severity were independent statistical predictors of mortality, trauma-related pediatric acute respiratory distress syndrome was not (odds ratio, 2.35; 95% CI, 0.88-6.28; p = 0.087). CONCLUSIONS Pediatric acute respiratory distress syndrome is present in the pediatric trauma population. Trauma-related pediatric acute respiratory distress syndrome is associated with eight times the organ dysfunction and five times the mortality compared with patients without trauma-related pediatric acute respiratory distress syndrome, yet research in this area is lacking. Further prospective, mechanistic evaluations are essential to understand why these patients are at risk and how to effectively intervene to improve outcomes.

Background Predominance of 2 antigenically drifted influenza viruses during the 2019–2020 season offered an opportunity to assess vaccine effectiveness against life-threatening pediatric influenza disease from vaccine-mismatched viruses in the United States. Methods We enrolled children aged Results We enrolled 159 critically ill influenza case-patients (70% ≤8 years; 51% A/H1N1pdm09 and 25% B-Victoria viruses) and 132 controls (69% were aged ≤8 years). Among 56 sequenced A/H1N1pdm09 viruses, 29 (52%) were vaccine-mismatched (A/H1N1pdm09/5A+156K) and 23 (41%) were vaccine-matched (A/H1N1pdm09/5A+187A,189E). Among sequenced B-lineage viruses, majority (30 of 31) were vaccine-mismatched. Effectiveness against critical influenza was 63% (95% confidence interval [CI], 38% to 78%) and similar by age. Effectiveness was 75% (95% CI, 49% to 88%) against life-threatening influenza vs 57% (95% CI, 24% to 76%) against non-life-threating influenza. Effectiveness was 78% (95% CI, 41% to 92%) against matched A(H1N1)pdm09 viruses, 47% (95% CI, –21% to 77%) against mismatched A(H1N1)pdm09 viruses, and 75% (95% CI, 37% to 90%) against mismatched B-Victoria viruses. Conclusions During a season when vaccine-mismatched influenza viruses predominated, vaccination was associated with a reduced risk of critical and life-threatening influenza illness in children.

Key Points Question What was the incidence of multisystem inflammatory syndrome in children (MIS-C) among persons with SARS-CoV-2 infection in the US during April to June 2020? Findings In this cohort study of 248 persons with MIS-C, MIS-C incidence was 5.1 persons per 1 000 000 person-months and 316 persons per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years. Incidence was higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons compared with White persons and in younger persons compared with older persons. Meaning These findings suggest that MIS-C was a rare complication of SARS-CoV-2 infection; further study is needed to understand why MIS-C incidence varied by race/ethnicity and age group., This cohort study examines the incidence of multisystem inflammatory syndrome in children among persons in the US with SARS-CoV-2 infection., Importance Multisystem inflammatory syndrome in children (MIS-C) is associated with recent or current SARS-CoV-2 infection. Information on MIS-C incidence is limited. Objective To estimate population-based MIS-C incidence per 1 000 000 person-months and to estimate MIS-C incidence per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years. Design, Setting, and Participants This cohort study used enhanced surveillance data to identify persons with MIS-C during April to June 2020, in 7 jurisdictions reporting to both the Centers for Disease Control and Prevention national surveillance and to Overcoming COVID-19, a multicenter MIS-C study. Denominators for population-based estimates were derived from census estimates; denominators for incidence per 1 000 000 SARS-CoV-2 infections were estimated by applying published age- and month-specific multipliers accounting for underdetection of reported COVID-19 case counts. Jurisdictions included Connecticut, Georgia, Massachusetts, Michigan, New Jersey, New York (excluding New York City), and Pennsylvania. Data analyses were conducted from August to December 2020. Exposures Race/ethnicity, sex, and age group (ie, ≤5, 6-10, 11-15, and 16-20 years). Main Outcomes and Measures Overall and stratum-specific adjusted estimated MIS-C incidence per 1 000 000 person-months and per 1 000 000 SARS-CoV-2 infections. Results In the 7 jurisdictions examined, 248 persons with MIS-C were reported (median [interquartile range] age, 8 [4-13] years; 133 [53.6%] male; 96 persons [38.7%] were Hispanic or Latino; 75 persons [30.2%] were Black). The incidence of MIS-C per 1 000 000 person-months was 5.1 (95% CI, 4.5-5.8) persons. Compared with White persons, incidence per 1 000 000 person-months was higher among Black persons (adjusted incidence rate ratio [aIRR], 9.26 [95% CI, 6.15-13.93]), Hispanic or Latino persons (aIRR, 8.92 [95% CI, 6.00-13.26]), and Asian or Pacific Islander (aIRR, 2.94 [95% CI, 1.49-5.82]) persons. MIS-C incidence per 1 000 000 SARS-CoV-2 infections was 316 (95% CI, 278-357) persons and was higher among Black (aIRR, 5.62 [95% CI, 3.68-8.60]), Hispanic or Latino (aIRR, 4.26 [95% CI, 2.85-6.38]), and Asian or Pacific Islander persons (aIRR, 2.88 [95% CI, 1.42-5.83]) compared with White persons. For both analyses, incidence was highest among children aged 5 years or younger (4.9 [95% CI, 3.7-6.6] children per 1 000 000 person-months) and children aged 6 to 10 years (6.3 [95% CI, 4.8-8.3] children per 1 000 000 person-months). Conclusions and Relevance In this cohort study, MIS-C was a rare complication associated with SARS-CoV-2 infection. Estimates for population-based incidence and incidence among persons with infection were higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons. Further study is needed to understand variability by race/ethnicity and age group.

Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children, No therapies for acute coronavirus disease 2019 (COVID-19) have been tested in children to establish effectiveness. Despite this, across 48 hospitals, 235/424 children (55%) admitted to the intensive care or step-down unit with COVID-19 received directed therapies. Systemic steroids and remdesivir were most commonly administered, with use rising from March 2020 to December 2020.

Careful airway risk assessment and procedural planning are vital to ensure patients' safety during airway management. Patients with known procedural difficulty during previous airway management or new anatomical changes pose challenges and risks. To improve communication and the value of documented information regarding difficult airway management for future clinical encounters, we utilized existing electronic health record functions to develop a "difficult airway Navigator." We describe this tool's creation and implementation, which allows clinicians to readily review past airway information and efficiently create difficult airway notes, bedside signs, flags, and orders.

Recent clinical trials have moved iodine-131 (I-131) metaiodobenzylguanidine (MIBG) therapy into frontline management of high-risk neuroblastoma. With this expansion, it is reasonable to anticipate the need for intensive care level resuscitations. Radiation exposure remains the greatest risk to health care professionals managing these patients. We combined shock simulation scenario data with actual radiation dosimetry data to create a care model allowing for aggressive, prolonged in situ resuscitation of a critically ill pediatric patient after I-131 MIBG administration. This model will maintain a critical care provider's radiation level below 10% of the annual occupational dose limit (5 mSv, 500 mrem) per patient managed.

Severe acute respiratory syndrome coronavirus 2 is a novel cause of organ dysfunction in children, presenting as either coronavirus disease 2019 with sepsis and/or respiratory failure or a hyperinflammatory shock syndrome. Clinicians must now consider these diagnoses when evaluating children for septic shock and sepsis-associated organ dysfunction. The Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children provide an appropriate framework for the early recognition and initial resuscitation of children with sepsis or septic shock caused by all pathogens, including severe acute respiratory syndrome coronavirus 2. However, the potential benefits of select adjunctive therapies may differ from non-coronavirus disease 2019 sepsis.

OBJECTIVES The 2015 definition for pediatric acute respiratory distress syndrome did not require the presence of bilateral infiltrates. We tested the hypothesis that pediatric patients meeting oxygenation criteria for pediatric acute respiratory distress syndrome but without bilateral infiltrates would have different inflammatory biomarker levels and clinical outcomes than those with bilateral infiltrates. DESIGN Secondary analysis of a prospective cohort study. SETTING Twenty-two PICUs. PATIENTS Four-hundred forty-six patients age 2 weeks to 17 years intubated for respiratory failure with oxygenation index greater than or equal to 4 or oxygenation saturation index greater than or equal to 5 on the day of intubation or the day after. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients with bilateral infiltrates, either on the day of intubation or within the following 2 days, were compared with children who never developed bilateral infiltrates. Two analyses were performed to test 1) whether bilateral infiltrates are associated with elevated interleukin-1 receptor antagonist or interleukin-8 and 2) whether bilateral infiltrates are associated with worse clinical outcomes. Patients with bilateral infiltrates more often had a primary diagnosis of pneumonia (41% vs 28%; p = 0.02) and less often asthma (8% vs 23%; p < 0.01). After controlling for age, gender, and primary diagnosis, interleukin-1 receptor antagonist was higher on study days 1 and 2 in patients with bilateral infiltrates. There was no difference in interleukin-8 levels. After adjusting for age, gender, Pediatric Risk of Mortality score, and severity of oxygenation defect, presence of bilateral infiltrates was associated with longer duration of mechanical ventilation in survivors (hazard ratio, 0.64; 95% CI, 0.49-0.82; p < 0.01); this association was independent of primary diagnosis. Overall mortality was 9%; mortality was higher in those without bilateral infiltrates (14% vs 8%; p = 0.04). CONCLUSIONS Children meeting pediatric acute respiratory distress syndrome oxygenation criteria with bilateral infiltrates on chest radiograph experience a more intense early inflammatory response. Bilateral infiltrates are associated with longer time on the ventilator independent of oxygenation defect severity.

Objectives No gold standard for ideal body weight determination in children exists. We aimed to compare four methods of ideal body weight calculation and determine level of agreement between methods and impact of measurement variance on tidal volumes prescribed in mechanically ventilated pediatric acute respiratory distress syndrome. Design Post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies. Setting Twenty-six academic PICUs. Patients Five hundred eighty-nine patients. Interventions None. Measurements and main results Ideal body weight was calculated by four common methods: National Center for Health Statistics, McLaren, Moore, and body mass index, and compared in three ways: 1) determine the proportion of the cohort for which each method could successfully calculate ideal body weight; 2) compare the level of agreement between the ideal body weight methods by Bland-Altman analysis; and 3) evaluate the difference in tidal volume when 6 mL/kg ideal body weight was prescribed. We a priori defined the better method to be one that could calculate ideal body weight in most subjects, had good agreement with other methods, and led to a lower tidal volume. Only 55% could have ideal body weight measured by all four methods. National Center for Health Statistics, McLaren, and Moore methods could calculate ideal body weight in greater than or equal to 90%, whereas body mass index method was successful in only 61% because of no body mass index validation in less than 2-year-olds. In comparing each method to the others, there was great variance, particularly in greater than or equal to 10-year-olds. This variance was greatest between Moore and body mass index methods with greater than or equal to 10 kg difference in ideal body weight in some subjects. The McLaren method had the best agreement with all other methods, and yielded similar prescribed tidal volume in 2- to 10-year-olds and lower tidal volume in greater than or equal to 10 years old. Conclusions There is substantial variation in calculated ideal body weight among four commonly used methods, particularly in adolescents. Since varying ideal body weight may lead to discrepancies in pediatric acute respiratory distress syndrome care, a standard approach to ideal body weight measurement is needed. We recommend the McLaren method to calculate ideal body weight in children with pediatric acute respiratory distress syndrome until a gold standard method is validated.

Objectives Prolonged excessive endotracheal cuff pressure greater than 30 cmH2O is thought to cause ischemic airway injury. Excessive cuff pressure with altitude gain during air medical transport has been previously described in adult patients. It is poorly understood how pediatric-sized endotracheal tube (ETT) cuffs behave with atmospheric pressure change during flight. Methods In ex vivo models 4.0, 6.0, and 8.0, ETTs restricted within scaled syringe tubing were inflated to 20 cmH2O. Pressure was measured against 1500 ft elevation gain in ground and flight models. In an in vivo observation of pediatric patient transport, change in cuff pressure was measured between takeoff and helicopter peak flight altitudes. Results In the ex vivo ground model, endotracheal cuff pressure increased linearly with altitude and exceeded 40 cmH2O in all tube sizes. Comparable pressure change was demonstrated in the flight model. No difference was demonstrated in the degree of pressure change between ETT sizes. In the in vivo observations during patient transport, pressure increase was consistent with that seen in the ex vivo models. Conclusions Children who are intubated with cuffed ETTs for air medical transport are subject to excessive endotracheal cuff pressure at even low flight altitudes. Endotracheal tube size did not affect the degree of cuff pressure change, contrary to previous study. These findings need to be validated and correlated to patient clinical outcomes. The implications of these data need to be considered clinically particularly for prolonged transport of intubated pediatric patients at elevation.

Objectives The impact of extrapulmonary organ dysfunction, independent from sepsis and lung injury severity, on outcomes in pediatric acute respiratory failure is unclear. We sought to determine the frequency, timing, and risk factors for extrapulmonary organ dysfunction and the independent association of multiple organ dysfunction syndrome with outcomes in pediatric acute respiratory failure. Design Secondary observational analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure cluster-randomized prospective clinical trial conducted between 2009 and 2013. Setting Thirty-one academic PICUs in the United States. Patients Two thousand four hundred forty-nine children mechanically ventilated for acute respiratory failure enrolled in Randomized Evaluation of Sedation Titration for Respiratory Failure. Measurements and main results Organ dysfunction was defined using criteria published for pediatric sepsis. Multiple organ dysfunction syndrome was defined as respiratory dysfunction one or more extrapulmonary organ dysfunctions. We used multivariable logistic regression to identify risk factors for multiple organ dysfunction syndrome, and logistic or proportional hazards regression to compare clinical outcomes. All analyses accounted for PICU as a cluster variable. Overall, 73% exhibited extrapulmonary organ dysfunction, including 1,547 (63%) with concurrent multiple organ dysfunction syndrome defined by onset on day 0/1 and 244 (10%) with new multiple organ dysfunction syndrome with onset on day 2 or later. Most patients (93%) with indirect lung injury from sepsis presented with concurrent multiple organ dysfunction syndrome, whereas patients with direct lung injury had both concurrent (56%) and new (12%) multiple organ dysfunction syndrome. Risk factors for concurrent multiple organ dysfunction syndrome included older age, illness severity, sepsis, cancer, and moderate/severe lung injury. Risk factors for new multiple organ dysfunction syndrome were moderate/severe lung injury and neuromuscular blockade. Both concurrent and new multiple organ dysfunction syndrome were associated with 90-day in-hospital mortality (concurrent: adjusted odds ratio, 6.54; 95% CI, 3.00-14.25 and new: adjusted odds ratio, 3.21; 95% CI, 1.48-6.93) after adjusting for sepsis, moderate/severe lung injury, and other baseline characteristics. Conclusions Extrapulmonary organ dysfunction was common, generally occurred concurrent with respiratory dysfunction (especially in sepsis), and was a major risk factor for mortality in pediatric acute respiratory failure.

In 2001, the Surviving Sepsis Campaign (SSC) began to develop evidence-based guidelines and recommendations for the resuscitation and management of patients with sepsis. With the 2016 edition, the Society of Critical Care Medicine and European Society of Intensive Care Medicine recommended a separate task force be dedicated to guideline formulation for children. The objective of the “Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children” is to provide guidance for the care of infants, children, and adolescents with septic shock and other sepsis-associated organ dysfunction. Recommendations are intended to guide “best practice” rather than to establish a treatment algorithm or to define standard of care and cannot replace the clinician's decision-making capability when presented with a patient's unique set of clinical variables.

Contains fulltext : 230013.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research. 01 februari 2020

Elevated surfactant protein D (SP-D) is a relatively specific indicator of lung injury and is associated with both acute and chronic lung disease in adults and respiratory distress syndrome in premature infants. The relationship between plasma SP-D and lung injury in children with acute respiratory failure is unclear.Is plasma SP-D associated with lung injury or outcome in children with acute respiratory failure?This was a prospective cohort study in children 2 weeks to 17 years of age with acute respiratory failure who participated in the BALI multi-center study. Analyses were done using SP-D levels in plasma from the first sample taken on either the day of intubation or one of the following 2 days. SP-D level was measured by enzyme-linked immunosorbent assay.Plasma samples from 350 patients were used in the analysis; 233 had pediatric ARDS (PARDS). SP-D levels varied across primary diagnoses (P .001). Elevated SP-D levels were associated with severe PARDS after adjusting for age, pediatric risk of mortality III (PRISM-III), and primary diagnosis (OR = 1.02; CI = 1.01-1.04; P = .011). Multivariable analyses also indicated that elevated SP-D levels were associated with death (OR = 1.02; CI = 1.01-1.04; P = .004), duration of mechanical ventilation (P = .012), PICU length of stay (P = .019), and highest oxygenation index (P = .040). SP-D levels also correlated with age (rElevated plasma SP-D levels are associated with severe PARDS and poor outcomes in children with acute respiratory failure. Future studies will determine whether SP-D can be used to predict the degree of lung injury or response to treatment and whether SP-D is useful in identifying PARDS endotypes.

Background The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure. Methods This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped. Results Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4–12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level. Conclusions When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted. Electronic supplementary material The online version of this article (10.1186/s13054-019-2342-8) contains supplementary material, which is available to authorized users.

IMPORTANCE: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. OBJECTIVE: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. SETTING, DESIGN, AND PARTICIPANTS: Case series of patients (age

Alternative locations for children near end of life (EOL) are lacking in the United States with deaths largely occurring within intensive care units (ICUs). The reflection room (RR) was implemented as a relevant space for providing this care in our hospital.We hypothesized staff would report a positive experience in providing EOL and/or postmortem (PM) care here and would recommend this to peers.This explorative study summarized room use data and evaluated staff experiences using a voluntary qualitative and quantitative survey.The survey was administered to the inpatient interdisciplinary team.From 2011 to 2014, 116 children used the RR, 64% for PM care, and 34% for EOL care. A total of 201 staff responded to the survey. Of them, 90% described the space as a valuable resource to families, 90% reported a preference for using this location versus a hospital unit, and 93% stated they would encourage their peers to do the same. Advantages listed were increased privacy, allowance for more visitors, and a quieter, calmer environment. Challenges included distance from the unit of transfer, managing assignments in two hospital locations, and medication transportation. Overall, there was a measureable decrease in the number of deaths pronounced in the ICU as the number pronounced in the RR increased, illustrating a significant change in practice.This study demonstrated an overwhelmingly positive experience in providing EOL and/or PM care to children in the RR and staff would recommend this to peers. This model of care should be a serious consideration for hospitals in the United States.

ObjectivesTo determine the feasibility of pulmonary function and quality of life evaluations in children after acute respiratory distress syndrome.DesignA prospective follow-up feasibility study.SettingA tertiary PICU.PatientsChildren less than 18 years old with acute respiratory distress syndrome admitted between 2000 and 2005.InterventionPulmonary function testing and patient and parental quality of life surveys approximately 12-month after acute respiratory distress syndrome.Measurements and main resultsOne hundred eighty patients met acute respiratory distress syndrome criteria; 37 (20%) died, 90 (51%) declined participation, 28 (16%) consented but did not return, and 24 (13%) returned for follow-up visit. Twenty-three patients completed quality of life testing and 17 completed pulmonary functions. Clinical characteristics of those who returned were no different from those who did not except for age (median age, 4.9 vs 1.8 yr). One-third had mild to moderate pulmonary function deficits. Quality of life scores were marginal with general health perception, physical functioning, and behavior being areas of concern. These scores were lower than scores in children with chronic asthma. Parental quality of life assessments report lower scores in single-parent homes but no differences were noted by race or parental employment status.ConclusionsValuable information may be discerned from acute respiratory distress syndrome patients who return for follow-up evaluation. In this pilot study, up to one-third of children with acute respiratory distress syndrome exhibit pulmonary function deficits and 12-month postillness quality of life scores are lower than in children with chronic asthma. Parental perceptions of postillness quality of life may be negatively impacted by socioeconomic constraints. Long-term follow of children with acute respiratory distress syndrome is feasible and bears further investigation.

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.

To compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy.This study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category ≥3 were defined as subjects with cognitive impairment, and differences between groups were explored using regression methods accounting for pediatric intensive care unit as a cluster variable.This study identified 412 subjects (17%) with cognitive impairment. Compared with neurotypical subjects, subjects with cognitive impairment were older (median, years, 6.2 vs 1.4; P .001) with more severe pediatric acute respiratory distress syndrome (40% vs 33%; P = .009). They received significantly lower cumulative doses of opioids (median, mg/kg, 14.2 vs 16.2; P .001) and benzodiazepines (10.6 vs 14.4; P .001). Three nonverbal subjects with cognitive impairment received no analgesia or sedation. Subjects with cognitive impairment were assessed as having more study days awake and calm and fewer study days with an episode of pain. They were less likely to be assessed as having inadequate pain/sedation management or unplanned endotracheal/invasive tube removal. Subjects with cognitive impairment had more documented iatrogenic withdrawal symptoms than neurotypical subjects.Subjects with cognitive impairment in this study received less medication, but it is unclear whether they have authentically lower analgesic and/or sedative requirements or are vulnerable to inadequate assessment of discomfort because of the lack of validated assessment tools. We recommend the development of pain and sedation assessment tools specific to this patient population.

Two infants with disseminated adenoviral infections are described. Both these infants had a similar clinical course and were also diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH). Previous reports of immunocompromised adults with adenovirus-associated HLH are in the literature; however, this is the first report that we are aware of with this pathology occurring in infants. These cases are used to demonstrate the importance of thinking about HLH in patients who are diagnosed with adenovirus and exhibit prolonged fevers that are unresponsive to antimicrobial agents with hepatosplenomegaly and cytopenias.

Because of centralization of care, pediatric patients often require transfer for subspecialty care. We evaluated the impact of telemedicine critical care consultation and a pediatric hospitalist program on enabling patients to remain at a community hospital.This is a retrospective chart review of pediatric patients at a community hospital receiving critical care consultation from a tertiary children's hospital from January 2006 to October 2009. Patient cohorts differed by modality of intensivist consultation (telephone versus telemedicine) and modality of inpatient ward care at the community hospital (primary care physician versus hospitalist). Patients were compared for differences in transfer rate and rate of diversion from the pediatric intensive care unit to the tertiary ward.One hundred fifty-three charts were analyzed: 41 from prior to hospitalist and telemedicine implementation (Cohort 1), 56 from post-implementation of telemedicine but pre-hospitalist program (Cohort 2), and 56 after implementation of both the telemedicine and hospitalist programs (Cohort 3). Baseline data did not differ among cohorts. Transfer rates after intensivist consultation were lower after implementation of telemedicine consultation (100%, 85.7%, and 87.5% in Cohorts 1-3, respectively; p=0.04). The proportion of transferred patients who were diverted to the tertiary ward decreased over time (19.5%, 14.5%, and 6.1% in Cohorts 1-3, respectively; p=0.003).Telemedicine consultation between pediatric intensivists and community hospital physicians combined with a pediatric hospitalist program at the community hospital has the potential to improve triage of pediatric patients and reduce the need to transfer patients.

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.

Objective The aim of the study was to assess the association of initial lactate (L0) with mortality in children with severe sepsis. Methods This prospective cohort study included 74 patients younger than 18 years with severe sepsis admitted to the pediatric intensive care unit (PICU) of a tertiary, academic children's hospital with lactate measured within 3 hours of meeting severe sepsis or septic shock. The primary outcome was in-hospital mortality. The secondary outcomes included PICU and hospital length of stay. Results Although overall mortality was 10.5% (n = 18), patients with L0 measured (n = 72) had a higher mortality (16% vs 6%, P = 0.03) and higher median PRISM-III risk of mortality scores (P = 0.02) than those who did not. Median L0 was no different between nonsurvivors and survivors (3.6 mmol/L [interquartile range, 2.0-9.0] in nonsurvivors vs 2.3 mmol/L [interquartile range, 1.4-3.5] in survivors, P = 0.11). However, L0 was independently associated with PRISM-III score (coefficient, 1.12; 95% confidence interval, 0.4-1.8; P = 0.003) with an increase in mean PRISM-III score of 1.12 U for every 1 mmol/L increase in L0, with L0 accounting for 12% of the variability in PRISM-III scores between patients. There was no association between L0 and PICU or hospital length of stay. Conclusions Although our single center study did not demonstrate that an elevated early lactate is associated with mortality in pediatric severe sepsis, L0 did correlate strongly with PRISM-III, the most robust measure of mortality risk in pediatrics. Therefore, early lactate measurement may be important as an early biomarker of disease severity. These data should be validated in a larger, multicenter, prospective 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.

OBJECTIVE. We conducted a prospective, observational study in a tertiary care pediatric center to determine risk factors for the development of and outcomes from ventilator-associated pneumonia. METHODS. From November 2004 to June 2005, all NICU and PICU patients mechanically ventilated for >24 hours were eligible for enrollment after parental consent. The primary outcome measure was the development of ventilator-associated pneumonia, which was defined by both Centers for Disease Control and Prevention/National Nosocomial Infections Surveillance criteria and clinician diagnosis. Secondary outcome measures were length of mechanical ventilation, hospital and ICU length of stay, hospital cost, and death. RESULTS. Fifty-eight patients were enrolled. The median age was 6 months, and 57% were boys. The most common ventilator-associated pneumonia organisms identified were Gram-negative bacteria (42%), Staphylococcus aureus (22%), and Haemophilus influenzae (11%). On multivariate analysis, female gender, postsurgical admission diagnosis, presence of enteral feeds, and use of narcotic medications were associated with ventilator-associated pneumonia. Patients with ventilator-associated pneumonia had greater need for mechanical ventilation (12 vs 22 median ventilator-free days), longer ICU length of stay (6 vs 13 median ICU-free days), higher total median hospital costs ($308534 vs $252652), and increased absolute hospital mortality (10.5% vs 2.4%) than those without ventilator-associated pneumonia. CONCLUSIONS. In mechanically ventilated, critically ill children, those with ventilator-associated pneumonia had a prolonged need for mechanical ventilation, a longer ICU stay, and a higher mortality rate. Female gender, postsurgical diagnosis, the use of narcotics, and the use of enteral feeds were associated with an increased risk of developing ventilator-associated pneumonia in these patients.

We explored the hypothesis that marked decline in plasma zinc concentrations among critically ill children is related to shifts in metallothionein expression and inflammation.Prospective pilot study.Intensive care unit of tertiary care children's hospital.All children (18 yrs) with unadjusted Pediatric Risk of Mortality III score5 or at least one organ failure admitted to the pediatric intensive care unit from March through August 2006 were eligible for enrollment.After consent, blood samples were collected on days 1 and 3 of illness and analyzed for serum chemistries, plasma zinc and copper levels, metallothionein isoform expression, and cytokine levels.Twenty patients were enrolled, with median age of 2.9 yrs (interquartile range, 0.7-10.1). Male to female ratio was 1.2:1. All patients had low zinc levels (mean, 0.43; range, 0.26-0.66 mug/dL) on day 1 of pediatric intensive care unit admission, and remained low (mean, 0.51; range, 0.26-0.81 mug/dL) on day 3, even when corrected for hypoalbuminemia. In comparison, serum copper levels were normal. On day 1, there was a positive correlation between zinc levels and expression of MT-1A (p0.01), MT-1G (p = 0.02), and MT-1H (p = 0.03). Plasma zinc levels correlated inversely with C-reactive protein levels (r = -.75, p = 0.01) and interleukin-6 levels (r = -.53, p = 0.04) on day 3. On day 3, patients with two or more organ failures had significantly lower plasma zinc concentrations compared with patients with/=1 organ failure (p = 0.03).Plasma zinc concentrations are low in critically ill children. Plasma zinc correlated with measures of inflammation (C-reactive protein and interleukin-6) on day 3; low plasma zinc concentrations were associated with the degree of organ failure on day 3. These data serve as the basis for a larger study of shifts in plasma zinc concentrations in critically children to potentially identify patients who might benefit from zinc supplementation.

Von Willebrand factor antigen (vWF-Ag) is a marker of pulmonary and systemic endothelial activation and injury. Adult studies indicate that patients with plasma vWF-Ag levelsor = 450% of control early in the course of acute lung injury (ALI) have an increased risk of death. The objective of this study was to evaluate whether vWF-Ag is elevated in the early phase of ALI in children and whether the magnitude of the increase was predictive of two important outcomes: mortality or duration of mechanical ventilation.Two-center, prospective observational study.Two pediatric intensive care units: one in an academic university setting and one in a major community children's hospital.After appropriate consent, plasma was collected from 48 pediatric patients on day 1 of ALI, 45 patients on day 2 of ALI, and four intubated controls.None.Mean PaO2/FiO2 at the onset of ALI was 140 +/- 70, and mortality rate was 17%. vWF-Ag levels on day 1 of ALI were higher in patients compared with controls (287 +/- 183 vs. 87 +/- 84% of control [mean +/- SD], p.05). Patients with vWF-Ag levelsor = 450% of control on day 1 of ALI had a markedly greater risk of death (odds ratio, 7.0; confidence interval, 1.31, 37.30; p.05). Multivariate analysis revealed that elevated vWF-Ag level and either presence of multiple organ system failure or Pediatric Risk of Mortality III score independently predict increased risk of death. vWF-Ag levels on day 2 of ALI were significantly higher in patients who required prolonged mechanical ventilation (316 +/- 173 vs. 191 +/- 89% of control, p.05).Early injury to the systemic and pulmonary endothelium, as measured by plasma vWF-Ag levels, is associated with an increased risk of death and prolonged mechanical ventilation in pediatric patients with ALI.

Introduction The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS. Methods We conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates. Results Plasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman’s rho = 0.37, p p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury. Conclusion Elevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.

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.

The 1994 American European Consensus Committee definitions of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have not been applied systematically in the pediatric population.The purpose of this study was to evaluate prospectively the epidemiology and clinical risk factors associated with death and prolonged mechanical ventilation in all pediatric patients admitted to two large, pediatric intensive care units with ALI/ARDS using Consensus criteria.All pediatric patients meeting Consensus Committee definitions for ALI were prospectively identified and included in a relational database.There were 328 admissions for ALI/ARDS with a mortality of 22%. Multivariate logistic regression analyses revealed (1) the initial severity of oxygenation defect, as measured by the Pa(O2)/FI(O2) ratio; (2) the presence of nonpulmonary and non-central nervous system (CNS) organ dysfunction; and (3) the presence of CNS dysfunction were independently associated with mortality and prolonged mechanical ventilation. A substantial fraction of patients (28%) did not require mechanical ventilation at the onset of ALI; 46% of these patients eventually required intubation for worsening ALI.Mortality in pediatric ALI/ARDS is high and several risk factors have major prognostic value. In contrast to ALI/ARDS in adults, the initial severity of arterial hypoxemia in children correlates well with mortality. A significant fraction of patients with pediatric ALI/ARDS can be identified before endotracheal intubation is required. These patients provide a valuable group in whom new therapies can be tested.