Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC ...products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient‐specific risk factors. Unpacking these complexities requires an in‐depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion‐related immunomodulation and provide suggestions for future research directions.
The unique characteristics of pulmonary circulation and alveolar-epithelial capillary-endothelial barrier allow for maintenance of the air-filled, fluid-free status of the alveoli essential for ...facilitating gas exchange, maintaining alveolar stability, and defending the lung against inhaled pathogens. The hallmark of pathophysiology in acute respiratory distress syndrome is the loss of the alveolar capillary permeability barrier and the presence of protein-rich edema fluid in the alveoli. This alteration in permeability and accumulation of fluid in the alveoli accompanies damage to the lung epithelium and vascular endothelium along with dysregulated inflammation and inappropriate activity of leukocytes and platelets. In addition, there is uncontrolled activation of coagulation along with suppression of fibrinolysis and loss of surfactant. These pathophysiological changes result in the clinical manifestations of acute respiratory distress syndrome, which include hypoxemia, radiographic opacities, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. Resolution of acute respiratory distress syndrome involves the migration of cells to the site of injury and re-establishment of the epithelium and endothelium with or without the development of fibrosis. Most of the data related to acute respiratory distress syndrome, however, originate from studies in adults or in mature animals with very few studies performed in children or juvenile animals. The lack of studies in children is particularly problematic because the lungs and immune system are still developing during childhood and consequently the pathophysiology of pediatric acute respiratory distress syndrome may differ in significant ways from that seen in acute respiratory distress syndrome in adults. This article describes what is known of the pathophysiologic processes of pediatric acute respiratory distress syndrome as we know it today while also presenting the much greater body of evidence on these processes as elucidated by adult and animal studies. It is also our expressed intent to generate enthusiasm for larger and more in-depth investigations of the mechanisms of disease and repair specific to children in the years to come.
To review the literature for studies published in children on the pathobiology, severity, and risk stratification of pediatric acute respiratory distress syndrome (PARDS) with the intent of guiding ...current medical practice and identifying important areas for future research related to severity and risk stratification.
Electronic searches of PubMed and Embase were conducted from 2013 to March 2022 by using a combination of medical subject heading terms and text words to capture the pathobiology, severity, and comorbidities of PARDS.
We included studies of critically ill patients with PARDS that related to the severity and risk stratification of PARDS using characteristics other than the oxygenation defect. Studies using animal models, adult only, and studies with 10 or fewer children were excluded from our review.
Title/abstract review, full-text review, and data extraction using a standardized data collection form.
The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize relevant evidence and develop recommendations for clinical practice. There were 192 studies identified for full-text extraction to address the relevant Patient/Intervention/Comparator/Outcome questions. One clinical recommendation was generated related to the use of dead space fraction for risk stratification. In addition, six research statements were generated about the impact of age on acute respiratory distress syndrome pathobiology and outcomes, addressing PARDS heterogeneity using biomarkers to identify subphenotypes and endotypes, and use of standardized ventilator, physiologic, and nonpulmonary organ failure measurements for future research.
Based on an extensive literature review, we propose clinical management and research recommendations related to characterization and risk stratification of PARDS severity.
We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress ...syndrome (PARDS), considering new evidence and topic areas that were not previously addressed.
International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science.
Not applicable.
Patients with or at risk for PARDS.
None.
Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%.
PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.
Objective: Delirium is a common problem in the Pediatric Intensive Care Unit (PICU) and is associated with increased length of stay, cost and mortality. This study evaluated the relationship between ...noise pollution and delirium risk. Design: This is a Quality Improvement (QI) initiative at an academic PICU. Sound levels were monitored and patients were screened for delirium using the Cornell Assessment of Pediatric Delirium (CAPD). Setting PICU Patients: All PICU patients Interventions: None Measurements and Main Results: Over the 83-week study period (2015-2017), the median IQR CAPD score was 8 3 to 14. Nursing compliance with the CAPD was 72.2%. The proportion of patients screening positive for delirium (CAPD ≥ 9) was 45.9%. A total of 329 711 hly decibel (dB) measurements were collected and reported. Occupied rooms were louder than unoccupied rooms (51.8 51.6-51.9 dB vs. 49.8 49.7-49.9 dB, respectively, p < 0.001). Days (10 AM to 4 PM) were louder than nights (11 PM to 5 AM) (52.8 52.7-53.0 dB vs. 50.7 49.9-51.5 dB, respectively p < 0.001) in occupied rooms. Winter (Nov-Feb) months were louder than summer (May-Aug) months (52.0 51.8-52.3 dB vs. 51.5 51.3-51.7 dB, respectively, p < 0.002) in occupied rooms. Median weekly nighttime noise levels and CAPD scores demonstrated a correlation coefficient of 0.6 (p < 0.001). Median weekly risk of mortality (ROM) and CAPD scores demonstrated a correlation coefficient of 0.15 (p < 0.01). Conclusions: Significant noise pollution exists in the PICU with a moderate correlation between nighttime noise levels and CAPD scores. This could potentially implicate noise pollution as a risk factor for the development of delirium.
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.
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.
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.
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.
To determine the impact of patient-specific and disease-related characteristics on the severity of illness and on outcome in pediatric patients with acute respiratory distress syndrome with the ...intent of guiding current medical practice and identifying important areas for future research.
Electronic searches of PubMed, EMBASE, Web of Science, Cochrane, and Scopus were conducted. References were reviewed for relevance and features included in the following section.
Not applicable.
PICU patients with evidence of acute lung injury, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.
Not applicable.
The comorbidities associated with outcome in pediatric acute respiratory distress syndrome can be divided into 1) patient-specific factors and 2) factors inherent to the disease process. The primary comorbidity associated with poor outcome is preexisting congenital or acquired immunodeficiency. Severity of disease is often described by factors identifiable at admission to the ICU. Many measures that are predictive are influenced by the underlying disease process itself, but may also be influenced by nutritional status, chronic comorbidities, or underlying genetic predisposition. Of the measures available at the bedside, both PaO2/FIO2 ratio and oxygenation index are fairly consistent and robust predictors of disease severity and outcomes. Multiple organ system dysfunction is the single most important independent clinical risk factor for mortality in children at the onset of acute respiratory distress syndrome.
The assessment of oxygenation and ventilation indices simultaneously with genetic and biomarker measurements holds the most promise for improved risk stratification for pediatric acute respiratory distress syndrome patients in the very near future. The next phases of pediatric acute respiratory distress syndrome pathophysiology and outcomes research will be enhanced if 1) age group differences are examined, 2) standardized datasets with adequately explicit definitions are used, 3) data are obtained at standardized times after pediatric acute respiratory distress syndrome onset, and 4) nonpulmonary organ failure scores are created and implemented.
Abstract
Background
Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. ...Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction.
Methods
This was a prospective observational study of 432 patients aged 2 weeks—17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses.
Results
sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (
n
= 432, adjusted HR = 1.003,
p
= 0.02) and worse OI in the first 5 days after intubation (
n
= 252, Estimate = 0.02,
p
< 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003,
p
< 0.0001; and slope, Estimate = 0.01,
p
= 0.0009,
n
= 386).
Conclusions
Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies.
Trial registration
:
https://clinicaltrials.gov/ct2/show/NCT00814099
.
In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.
Few data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS).
To describe contemporary use of adjunctive therapies for early PARDS as a framework for ...future investigations.
This was a preplanned substudy of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks.
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.
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.
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