Evaluating the Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) for Clinical Trials of Antibiotics in Pediatric Pneumonia.

Objective outcomes for pediatric community-acquired pneumonia (CAP) are lacking. The desirability of outcome ranking (DOOR) and response adjusted for duration of antibiotic risk (RADAR) outcome encompass clinical benefit and adverse effects, while also accounting for antibiotic exposure. We evaluated DOOR/RADAR through simulations and compared sample size considerations to non-inferiority designs in a hypothetical trial comparing antibiotics to no antibiotics (i.e., placebo) for children with mild CAP. We also evaluated a trial comparing different durations of antibiotics. Three scenarios were considered - one with no difference in DOOR between the two groups, one in which placebo is more efficacious, and another in which amoxicillin is more efficacious than placebo. Power to detect a difference between arms was greater using DOOR/RADAR compared to DOOR. Assuming a sample size of 200, DOOR had 2.5%, 50%, and 65% power to detect a statistical difference between arms for Scenarios 1-3, respectively, significantly less than DOOR/RADAR. Importantly, DOOR/RADAR incorrectly identified placebo as superior in Scenario 3 where amoxicillin was truly efficacious. Sample size requirements for non-inferiority designs were larger to achieve similar levels of power as DOOR and DOOR/RADAR. DOOR/RADAR has the potential to lead to an incorrect conclusion declaring placebo superior when amoxicillin is efficacious.

Risk factors for prolonged infection and secondary infection in pediatric severe sepsis.

PURPOSE: Sepsis causes significant worldwide morbidity and mortality. Inability to clear an infection and secondary infections are known complications in severe sepsis and likely result in worsened outcomes. We sought to characterize risk factors of these complications. METHODS: We performed a secondary analysis of clinical data from 401 subjects enrolled in the PHENOtyping sepsis-induced Multiple organ failure Study. We examined factors associated with prolonged infection, defined as infection that continued to be identified 7 days or more from initial identification, and secondary infection, defined as new infections identified ≥ 3 days from presentation. Multivariable adjustment was performed to examine laboratory markers of immune depression, with immunocompromised and immunocompetent subjects analyzed separately. RESULTS: Illness severity, immunocompromised status, invasive procedures, and site of infection were associated with secondary infection and/or prolonged infection. Persistent lymphopenia, defined as an absolute lymphocyte count (ALC) < 1000 cells/µL twice in the first five days, and persistent neutropenia, defined as absolute neutrophil count (ANC) < 1000 cells/µL twice in the first five days, were associated with secondary and prolonged infections. When adjusted in multivariable analysis, persistent lymphopenia remained associated with secondary infection in both immunocompromised (aOR = 14.19, 95% CI [2.69, 262.22] and immunocompetent subjects (aOR = 2.09, 95% CI [1.03, 4.17]). Persistent neutropenia was independently associated with secondary infection in immunocompromised subjects (aOR = 5.34, 95% CI [1.92, 15.84]). Secondary and prolonged infections were associated with worse outcomes, including death. CONCLUSIONS: Laboratory markers of immune suppression can be used to predict secondary infection. Lymphopenia is an independent risk factor in immunocompromised and immunocompetent patients for secondary infection.

Association of an In-Hospital Desirability of Outcomes Ranking Scale With Postdischarge Health-Related Quality of Life: A Secondary Analysis of the Life After Pediatric Sepsis Evaluation.

OBJECTIVES: To develop a desirability of outcome ranking (DOOR) scale for use in children with septic shock and determine its correlation with a decrease in 3-month postadmission health-related quality of life (HRQL) or death. DESIGN: Secondary analysis of the Life After Pediatric Sepsis Evaluation prospective study. SETTING: Twelve U.S. PICUs, 2013-2017. PATIENTS: Children (1 mo-18 yr) with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied a 7-point pediatric critical care (PCC) DOOR scale: 7: death; 6: extracorporeal life support; 5: supported by life-sustaining therapies (continuous renal replacement therapy, vasoactive, or invasive ventilation); 4: hospitalized with or 3: without organ dysfunction; 2: discharged with or 1: without new morbidity to patients by assigning the highest applicable score on specific days post-PICU admission. We analyzed Spearman rank-order correlations (95% CIs) between proximal outcomes (PCC-DOOR scale on days 7, 14, and 21, ventilator-free days, cumulative 28-day Pediatric Logistic Organ Dysfunction-2 (PELOD-2) scores, and PICU-free days) and 3-month decrease in HRQL or death. HRQL was measured by Pediatric Quality of Life Inventory 4.0 or Functional Status II-R for patients with developmental delay. Patients who died were assigned the worst possible HRQL score. PCC-DOOR scores were applied to 385 patients, median age 6 years (interquartile range 2, 13) and 177 (46%) with a complex chronic condition(s). Three-month outcomes were available for 245 patients (64%) and 42 patients (17%) died. PCC-DOOR scale on days 7, 14, and 21 demonstrated fair correlation with the primary outcome (-0.42 [-0.52, -0.31], -0.47 [-0.56, -0.36], and -0.52 [-0.61, -0.42]), similar to the correlations for cumulative 28-day PELOD-2 scores (-0.51 [-0.59, -0.41]), ventilator-free days (0.43 [0.32, 0.53]), and PICU-free days (0.46 [0.35, 0.55]). CONCLUSIONS: The PCC-DOOR scale is a feasible, practical outcome for pediatric sepsis trials and demonstrates fair correlation with decrease in HRQL or death at 3 months.

Social Determinants of Health and Health-Related Quality of Life Following Pediatric Septic Shock: Secondary Analysis of the Life After Pediatric Sepsis Evaluation Dataset, 2014-2017.

OBJECTIVES: Social determinants of health (SDOH) are associated with disparities in disease severity and in-hospital outcomes among critically ill children. It is unknown whether SDOH are associated with later outcomes. We evaluated associations between SDOH measures and mortality, new functional morbidity, and health-related quality of life (HRQL) decline among children surviving septic shock. DESIGN: Secondary analysis of the Life After Pediatric Sepsis Evaluation (LAPSE) prospective cohort study was conducted between 2014 and 2017. SETTING: Twelve academic U.S. PICUs were involved in the study. PATIENTS: Children younger than 18 years with community-acquired septic shock were involved in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed associations between race, ethnicity, income, education, marital status, insurance, language, and home U.S. postal code with day 28 mortality, new functional morbidity at discharge per day 28, and HRQL decline using logistic regression. Of 389 patients, 32% ( n = 98) of families had household income less than $50,000 per year. Median Pediatric Risk of Mortality (PRISM) score was 11 (interquartile range 6, 17). We found that English language and Area Deprivation Index less than 50th percentile were associated with higher PRISM scores. Mortality was 6.7% ( n = 26), new functional morbidity occurred in 21.8% ( n = 78) of patients, and HRQL decline by greater than 10% occurred in 31.0% of patients ( n = 63). We failed to identify any association between SDOH measures and mortality, new functional morbidity, or HRQL decline. We are unable to exclude the possibility that annual household income greater than or equal to $50,000 was associated with up to 81% lesser odds of mortality and, in survivors, more than three-fold greater odds of HRQL decline by greater than 10%. CONCLUSIONS: In this secondary analysis of the 2014-2017 LAPSE dataset, we failed to identify any association between SDOH measures and in-hospital or postdischarge outcomes following pediatric septic shock. This finding may be reflective of the high illness severity and single disease (sepsis) of the cohort, with contribution of clinical factors to functional and HRQL outcomes predominating over prehospital and posthospital SDOH factors.

Early Cardiac Arrest Hemodynamics, End-Tidal C o2 , and Outcome in Pediatric Extracorporeal Cardiopulmonary Resuscitation: Secondary Analysis of the ICU-RESUScitation Project Dataset (2016-2021).

OBJECTIVES: Cannulation for extracorporeal membrane oxygenation during active extracorporeal cardiopulmonary resuscitation (ECPR) is a method to rescue patients refractory to standard resuscitation. We hypothesized that early arrest hemodynamics and end-tidal C o2 (ET co2 ) are associated with survival to hospital discharge with favorable neurologic outcome in pediatric ECPR patients. DESIGN: Preplanned, secondary analysis of pediatric Utstein, hemodynamic, and ventilatory data in ECPR patients collected during the 2016-2021 Improving Outcomes from Pediatric Cardiac Arrest study; the ICU-RESUScitation Project (ICU-RESUS; NCT02837497). SETTING: Eighteen ICUs participated in ICU-RESUS. PATIENTS: There were 97 ECPR patients with hemodynamic waveforms during cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall, 71 of 97 patients (73%) were younger than 1 year old, 82 of 97 (85%) had congenital heart disease, and 62 of 97 (64%) were postoperative cardiac surgical patients. Forty of 97 patients (41%) survived with favorable neurologic outcome. We failed to find differences in diastolic or systolic blood pressure, proportion achieving age-based target diastolic or systolic blood pressure, or chest compression rate during the initial 10 minutes of CPR between patients who survived with favorable neurologic outcome and those who did not. Thirty-five patients had ET co2 data; of 17 survivors with favorable neurologic outcome, four of 17 (24%) had an average ET co2 less than 10 mm Hg and two (12%) had a maximum ET co2 less than 10 mm Hg during the initial 10 minutes of resuscitation. CONCLUSIONS: We did not identify an association between early hemodynamics achieved by high-quality CPR and survival to hospital discharge with favorable neurologic outcome after pediatric ECPR. Candidates for ECPR with ET co2 less than 10 mm Hg may survive with favorable neurologic outcome.

The Dual Task Ball Balancing Test and Its Association With Cognitive Function: Algorithm Development and Validation.

BACKGROUND: Dual task paradigms are thought to offer a quantitative means to assess cognitive reserve and the brain's capacity to allocate resources in the face of competing cognitive demands. The most common dual task paradigms examine the interplay between gait or balance control and cognitive function. However, gait and balance tasks can be physically challenging for older adults and may pose a risk of falls. OBJECTIVE: We introduce a novel, digital dual-task assessment that combines a motor-control task (the "ball balancing" test), which challenges an individual to maintain a virtual ball within a designated zone, with a concurrent cognitive task (the backward digit span task [BDST]). METHODS: The task was administered on a touchscreen tablet, performance was measured using the inertial sensors embedded in the tablet, conducted under both single- and dual-task conditions. The clinical use of the task was evaluated on a sample of 375 older adult participants (n=210 female; aged 73.0, SD 6.5 years). RESULTS: All older adults, including those with mild cognitive impairment (MCI) and Alzheimer disease-related dementia (ADRD), and those with poor balance and gait problems due to diabetes, osteoarthritis, peripheral neuropathy, and other causes, were able to complete the task comfortably and safely while seated. As expected, task performance significantly decreased under dual task conditions compared to single task conditions. We show that performance was significantly associated with cognitive impairment; significant differences were found among healthy participants, those with MCI, and those with ADRD. Task results were significantly associated with functional impairment, independent of diagnosis, degree of cognitive impairment (as indicated by the Mini Mental State Examination [MMSE] score), and age. Finally, we found that cognitive status could be classified with >70% accuracy using a range of classifier models trained on 3 different cognitive function outcome variables (consensus clinical judgment, Rey Auditory Verbal Learning Test [RAVLT], and MMSE). CONCLUSIONS: Our results suggest that the dual task ball balancing test could be used as a digital cognitive assessment of cognitive reserve. The portability, simplicity, and intuitiveness of the task suggest that it may be suitable for unsupervised home assessment of cognitive function.

Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children.

OBJECTIVES: Sepsis-associated immune suppression correlates with poor outcomes. Adult trials are evaluating immune support therapies. Limited data exist to support consideration of immunomodulation in pediatric sepsis. We tested the hypothesis that early, persistent lymphopenia predicts worse outcomes in pediatric severe sepsis. DESIGN: Observational cohort comparing children with severe sepsis and early, persistent lymphopenia (absolute lymphocyte count < 1,000 cells/µL on 2 d between study days 0-5) to children without. The composite outcome was prolonged multiple organ dysfunction syndrome (MODS, organ dysfunction beyond day 7) or PICU mortality. SETTING: Nine PICUs in the National Institutes of Health Collaborative Pediatric Critical Care Research Network between 2015 and 2017. PATIENTS: Children with severe sepsis and indwelling arterial and/or central venous catheters. INTERVENTIONS: Blood sampling and clinical data analysis. MEASUREMENTS AND MAIN RESULTS: Among 401 pediatric patients with severe sepsis, 152 (38%) had persistent lymphopenia. These patients were older, had higher illness severity, and were more likely to have underlying comorbidities including solid organ transplant or malignancy. Persistent lymphopenia was associated with the composite outcome prolonged MODS or PICU mortality (66/152, 43% vs 45/249, 18%; p < 0.01) and its components prolonged MODS (59/152 [39%] vs 43/249 [17%]), and PICU mortality (32/152, 21% vs 12/249, 5%; p < 0.01) versus children without. After adjusting for baseline factors at enrollment, the presence of persistent lymphopenia was associated with an odds ratio of 2.98 (95% CI [1.85-4.02]; p < 0.01) for the composite outcome. Lymphocyte count trajectories showed that patients with persistent lymphopenia generally did not recover lymphocyte counts during the study, had lower nadir whole blood tumor necrosis factor-α response to lipopolysaccharide stimulation, and higher maximal inflammatory markers (C-reactive protein and ferritin) during days 0-3 ( p < 0.01). CONCLUSIONS: Children with severe sepsis and persistent lymphopenia are at risk of prolonged MODS or PICU mortality. This evidence supports testing therapies for pediatric severe sepsis patients risk-stratified by early, persistent lymphopenia.

Predicting functional and quality-of-life outcomes following pediatric sepsis: performance of PRISM-III and PELOD-2.

BACKGROUND: Illness severity scores predict mortality following pediatric critical illness. Given declining PICU mortality, we assessed the ability of the Pediatric Risk of Mortality-III (PRISM) and Pediatric Logistic Organ Dysfunction-2 (PELOD) scores to predict morbidity outcomes. METHODS: Among 359 survivors <18 years in the Life After Pediatric Sepsis Evaluation multicenter prospective cohort study, we assessed functional morbidity at hospital discharge (Functional Status Scale increase ≥3 points from baseline) and health-related quality of life (HRQL; Pediatric Quality of Life Inventory or Functional Status II-R) deterioration >25% from baseline at 1, 3, 6, and 12 months post-admission. We determined discrimination of admission PRISM and admission, maximum, and cumulative 28-day PELOD with functional and HRQL morbidity at each timepoint. RESULTS: Cumulative PELOD provided the best discrimination of discharge functional morbidity (area under the receive operating characteristics curve [AUROC] 0.81, 95% CI 0.76-0.87) and 3-month HRQL deterioration (AUROC 0.71, 95% CI 0.61-0.81). Prediction was inferior for admission PRISM and PELOD and for 6- and 12-month HRQL assessments. CONCLUSIONS: Illness severity scores have a good prediction of early functional morbidity but a more limited ability to predict longer-term HRQL. Identification of factors beyond illness severity that contribute to HRQL outcomes may offer opportunities for intervention to improve outcomes. IMPACT: Illness severity scores are commonly used for mortality prediction and risk stratification in pediatric critical care research, quality improvement, and resource allocation algorithms. Prediction of morbidity rather than mortality may be beneficial given declining pediatric intensive care unit mortality. The PRISM and PELOD scores have moderate to good ability to predict new functional morbidity at hospital discharge following pediatric septic shock but limited ability to predict health-related quality of life outcomes in the year following PICU admission. Further research is needed to identify additional factors beyond illness severity that may impact post-discharge health-related quality of life.

Association of Sex and Age with Mortality and Health-Related Quality of Life in Children with Septic Shock: A Secondary Analysis of the Life After Pediatric Sepsis Evaluation.

Introduction: Sepsis is more common in males than females, but whether outcomes differ by sex in various pediatric age groups is unclear. The Life After Pediatric Sepsis Evaluation (LAPSE) was a multicenter prospective cohort study that evaluated health-related quality of life (HRQL) in children after community-acquired septic shock. In this secondary analysis, we evaluated whether male children are at increased risk of mortality or long-term decline in HRQL than female children by age group. Methods: Children (1 month-18 years) with community-acquired septic shock were recruited from 12 pediatric intensive care units in the U.S. Data included sex, age group (<1 year, 1-<13 years, 13-18 years), acute illness severity (acute organ dysfunction and inflammation), and longitudinal assessments of HRQL and mortality. Persistent decline in HRQL was defined as a 10% decrease in HRQL comparing baseline to 3 months following admission. Male and female children were stratified by age group and compared to evaluate the difference in the composite outcome of death or persistent decline in HRQL using the Cochran-Mantel-Haenszel test. Results: Of 389 children, 54.2% (n = 211) were male. Overall, 10% (21/211) of males and 12% (22/178) of females died by 3 months (p = 0.454). Among children with follow-up data, 41% (57/138) of males and 44% (48/108) of females died or had persistent decline in HRQL at 3 months (p = 0.636), with no observed difference by sex when stratified by age group. There was no significant difference in acute illness severity between males and females overall or stratified by age group. Conclusions: In this secondary analysis of the LAPSE cohort, HRQL, and mortality were not different between male and female children when stratified by age group. There were no significant differences by sex across multiple measures of illness severity or treatment intensity.

Change in Functional Status During Hospital Admission and Long-Term Health-Related Quality of Life Among Pediatric Septic Shock Survivors.

OBJECTIVES: To investigate whether change in functional status from pre-hospitalization baseline to hospital discharge is associated with long-term health-related quality of life (HRQL) among children surviving septic shock. DESIGN: Secondary analysis of Life After Pediatric Sepsis Evaluation (LAPSE), a prospective cohort study of children with community-acquired septic shock, enrolled from January 2014 to June 2017. SETTING: Twelve U.S. academic PICUs. PATIENTS: Children, 1 month to 18 years, who survived to hospital discharge and had follow-up data for HRQL at 3 and/or 12 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional Status Scale (FSS) was assessed around enrollment to ascertain baseline status (pre-hospitalization) and at 28 days or hospital discharge. Two measures of HRQL were utilized: children with significant development delay were measured with the Functional Status II-R (FSII-R); typically, developing children were measured with the Pediatric Quality of Life Inventory (PedsQL). Each group was analyzed separately with multivariable regression modeling to determine the association between change in FSS from baseline to day 28 and HRQL at 3 and 12 months from PICU admission. Of the original 389 LAPSE participants, 224 (58%) are included. Among children with developmental delay ( n = 88), worsened FSS was associated with lower FSII-R at 3 months from PICU admission (-2.02; 95% CI, -3.34 to -0.0.71; p = 0.003), but not 12 months. Among developmentally typical children ( n = 136), worsened FSS was associated with lower PedsQL at both 3 and 12 months. Developmentally typical children with a neurologic insult during the PICU stay had the largest decrement in PedsQL at 12 months (-14.04 mo; 95% CI, -22.15 to -5.94 mo; p < 0.001). However, worsened FSS remained associated with poor HRQL-PedsQL at 3 and 12 months, after controlling for neurologic events (both p < 0.001). CONCLUSIONS: Change in FSS during hospitalization for septic shock is associated with long-term reductions in HRQL and could serve as a useful tool for identifying children at risk for this sequela.

Fluid Balance and Its Association With Mortality and Health-Related Quality of Life: A Nonprespecified Secondary Analysis of the Life After Pediatric Sepsis Evaluation.

OBJECTIVES: To evaluate the association between fluid balance (FB) and health-related quality of life (HRQL) among children at 1 month following community-acquired septic shock. DESIGN: Nonprespecified secondary analysis of the Life After Pediatric Sepsis Evaluation. FB was defined as 100 × [(cumulative PICU fluid input - cumulative PICU fluid output)/PICU admission weight]. Three subgroups were identified: low FB (< 5%), medium FB (5%-15%), and high FB (> 15%) based on cumulative FB on days 0-3 of ICU stay. HRQL was measured at ICU admission and 1 month after using Pediatric Quality of Life Inventory 4.0 Generic Core or Infant Scales or the Stein-Jessop Functional Status Scale. The primary outcome was a composite of mortality or greater than 25% decline in HRQL 1 month after admission compared with baseline. SETTING: Twelve academic PICUs in the United States. PATIENTS: Critically ill children between 1 month and 18 years, with community-acquired septic shock who survived to at least day 4. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred ninety-three patients were included of whom 66 (23%) had low FB, 127 (43%) had medium FB, and 100 (34%) had high FB. There was no difference in Pediatric Risk of Mortality Score 3 (median 11 [6, 17]), age (median 5 [1, 12]), or gender (47% female) between FB groups. After adjusting for potential confounders and comparing with medium FB, higher odds of mortality or greater than 25% HRQL decline were seen in both the low FB (odds ratio [OR] 2.79 [1.20, 6.57]) and the high FB (OR 2.16 [1.06, 4.47]), p = 0.027. Compared with medium FB, low FB (OR 4.3 [1.62, 11.84]) and high FB (OR 3.29 [1.42, 8.00]) had higher odds of greater than 25% HRQL decline. CONCLUSIONS: Over half of the children who survived septic shock had low or high FB, which was associated with a significant decline in HRQL scores. Prospective studies are needed to determine if optimization of FB can improve HRQL outcomes.

Acute Disorders of Consciousness in Pediatric Severe Sepsis and Organ Failure: Secondary Analysis of the Multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study.

OBJECTIVES: Acute disorders of consciousness (DoC) in pediatric severe sepsis are associated with increased risk of morbidity and mortality. We sought to examine the frequency of and factors associated with DoC in children with sepsis-induced organ failure. DESIGN: Secondary analysis of the multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study (PHENOMS). SETTING: Nine tertiary care PICUs in the United States. PATIENTS: Children less than 18 years old admitted to a PICU with severe sepsis and at least one organ failure during a PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was frequency of DoC, defined as Glasgow Coma Scale (GCS) less than 12 in the absence of sedatives during an ICU stay, among children with severe sepsis and the following: single organ failure, nonphenotypeable multiple organ failure (MOF), MOF with one of the PHENOMS phenotypes (immunoparalysis-associated MOF [IPMOF], sequential liver failure-associated MOF, thrombocytopenia-associated MOF), or MOF with multiple phenotypes. A multivariable logistic regression analysis was performed to evaluate the association between clinical variables and organ failure groups with DoC. Of 401 children studied, 71 (18%) presented with DoC. Children presenting with DoC were older (median 8 vs 5 yr; p = 0.023), had increased hospital mortality (21% vs 10%; p = 0.011), and more frequently presented with both any MOF (93% vs 71%; p < 0.001) and macrophage activation syndrome (14% vs 4%; p = 0.004). Among children with any MOF, those presenting with DoC most frequently had nonphenotypeable MOF and IPMOF (52% and 34%, respectively). In the multivariable analysis, older age (odds ratio, 1.07; 95% CI, 1.01-1.12) and any MOF (3.22 [1.19-8.70]) were associated with DoC. CONCLUSIONS: One of every five children with severe sepsis and organ failure experienced acute DoC during their PICU stay. Preliminary findings suggest the need for prospective evaluation of DoC in children with sepsis and MOF.

Psychometric properties of light touch-pressure somatosensory measures in adults with neurological disorders: A systematic review.

OBJECTIVES: To critically appraise the psychometric properties of light touch-pressure somatosensory assessments to provide guidance for tool selection for research or clinical purposes. DATA SOURCES: MEDLINE, CINAHL, and PsycInfo were searched for research indexed from January 1990-November 2022. English language and human subject filters were applied. "Somatosensation", "psychometric property", and "nervous system-based health condition" search terms were combined. Grey literature and manual searches were conducted to ensure thoroughness. REVIEW METHODS: The reliability, construct validity, and/or measurement error of light touch-pressure assessments was reviewed in adult populations with neurological disorders. Reviewers individually extracted and managed data including patient demographics, assessment characteristics, statistical methods, and psychometric properties. Methodological quality of results was evaluated using an adapted version of the COnsensus-based Standards for the selection of health Measurement INstruments checklist. RESULTS: Thirty-three of 1938 articles were included for review. Fifteen light touch-pressure assessments demonstrated good or excellent reliability. Further, five of those 15 assessments achieved adequate validity and one of the 15 assessments achieved adequate measurement error. Over 80% of the summarized study ratings were determined to be of low or very low quality. CONCLUSION: We recommend using electrical perceptual tests, the Semmes-Weinstein Monofilaments, the Graded and Redefined Assessment of Strength, Sensibility, and Prehension, and the Moving Touch Pressure Test given that they demonstrated good to excellent results in three psychometric properties. No other assessment achieved adequate ratings in more than two psychometric properties. This review highlights a fundamental need to develop sensory assessments that are reliable, valid, and sensitive to change.

Radiographic pneumonia in young febrile infants presenting to the emergency department: secondary analysis of a prospective cohort study.

OBJECTIVE: The lack of evidence-based criteria to guide chest radiograph (CXR) use in young febrile infants results in variation in its use with resultant suboptimal quality of care. We sought to describe the features associated with radiographic pneumonias in young febrile infants. STUDY DESIGN: Secondary analysis of a prospective cohort study in 18 emergency departments (EDs) in the Pediatric Emergency Care Applied Research Network from 2016 to 2019. Febrile (≥38°C) infants aged ≤60 days who received CXRs were included. CXR reports were categorised as 'no', 'possible' or 'definite' pneumonia. We compared demographics, clinical signs and laboratory tests among infants with and without pneumonias. RESULTS: Of 2612 infants, 568 (21.7%) had CXRs performed; 19 (3.3%) had definite and 34 (6%) had possible pneumonias. Patients with definite (4/19, 21.1%) or possible (11/34, 32.4%) pneumonias more frequently presented with respiratory distress compared with those without (77/515, 15.0%) pneumonias (adjusted OR 2.17; 95% CI 1.04 to 4.51). There were no differences in temperature or HR in infants with and without radiographic pneumonias. The median serum procalcitonin (PCT) level was higher in the definite (0.7 ng/mL (IQR 0.1, 1.5)) vs no pneumonia (0.1 ng/mL (IQR 0.1, 0.3)) groups, as was the median absolute neutrophil count (ANC) (definite, 5.8 K/mcL (IQR 3.9, 6.9) vs no pneumonia, 3.1 K/mcL (IQR 1.9, 5.3)). No infants with pneumonia had bacteraemia. Viral detection was frequent (no pneumonia (309/422, 73.2%), definite pneumonia (11/16, 68.8%), possible pneumonia (25/29, 86.2%)). Respiratory syncytial virus was the predominant pathogen in the pneumonia groups and rhinovirus in infants without pneumonias. CONCLUSIONS: Radiographic pneumonias were uncommon in febrile infants. Viral detection was common. Pneumonia was associated with respiratory distress, but few other factors. Although ANC and PCT levels were elevated in infants with definite pneumonias, further work is necessary to evaluate the role of blood biomarkers in infant pneumonias.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials.

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Assessment of Patient Health-Related Quality of Life and Functional Outcomes in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: To describe health-related quality of life (HRQL) and functional outcomes in pediatric acute respiratory distress syndrome (ARDS) and to determine risk factors associated with poor outcome defined as death or severe reduction in HRQL at 28 days or ICU discharge. DESIGN: Prospective multisite cohort-outcome study conducted between 2019 and 2020. SETTING: Eight academic PICUs in the United States. PATIENTS: Children with ARDS based on standard criteria. INTERVENTIONS: Patient characteristics and illness severity were collected during PICU admission. Parent proxy-report measurements were obtained at baseline, day 28/ICU discharge, month 3, and month 9, utilizing Pediatric Quality of Life Inventory and Functional Status Scale (FSS). A composite outcome evaluated using univariate and multivariate analysis was death or severe reduction in HRQL (>25% reduction in the Pediatric Quality of Life Inventory at day 28/ICU discharge. MEASUREMENTS AND MAIN RESULTS: This study enrolled 122 patients with a median age of 3 years (interquartile range, 1-12 yr). Common etiologies of ARDS included pneumonia ( n = 63; 52%) and sepsis ( n = 27; 22%). At day 28/ICU discharge, half (50/95; 53%) of surviving patients with follow-up data reported a greater than 10% decrease in HRQL from baseline, and approximately one-third of participants ( n = 19/61; 31%) reported a greater than 10% decrease in HRQL at 9 months. Trends in FSS were similar. Of 104 patients with data, 47 patients (45%) died or reported a severe decrease of greater than 25% in HRQL at day 28/ICU discharge. Older age was associated with an increased risk of death or severe reduction in HRQL (odds ratio, 1.08; CI, 1.01-1.16). CONCLUSIONS: Children with ARDS are at risk for deterioration in HRQL and FSS that persists up to 9 months after ARDS. Almost half of children with ARDS experience a poor outcome including death or severe reduction in HRQL at day 28/ICU discharge.

Association of Pathogen Type With Outcomes of Children Encountering Community-Acquired Pediatric Septic Shock.

OBJECTIVES: To determine the association of pathogen type with mortality, functional status, and health-related quality of life (HRQL) among children at hospital discharge/1 month following hospitalization for septic shock. DESIGN: Secondary database analysis of a prospective, descriptive cohort investigation. SETTING: Twelve academic PICUs in the United States. PATIENTS: Critically ill children, 1 month to 18 years old, enrolled from 2013 to 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Association of clinical outcomes with pathogen type was assessed for all patients and separately for surviving patients enrolled in the primary Life After Pediatric Sepsis Evaluation (LAPSE) investigation. For this secondary analysis, we predicted that age would be associated with pathogen type and outcomes, and accordingly, it was incorporated as a confounding variable in primary analyses. Among 389 children enrolled with septic shock, at 1 month/hospital discharge, we observed no statistically significant differences in relation to pathogen types for the composite outcome mortality or substantial new functional morbidity: no causative organism identified (27% [28/103]), pure viral infections (26% [24/91]), pure bacterial/fungal infections (25% [31/125]), and bacterial/fungal+viral coinfections (33% [23/70]). Similarly, we observed no statistically significant differences in relation to pathogen types for the composite outcome, mortality, or persistent serious deterioration of HRQL: no causative organism identified (43% [44/103]), pure viral infections (33% [30/91]), pure bacterial/fungal infections (46% [57/125]), and bacterial/fungal+viral coinfections (43% [30/70]). However, we did identify statistically significant associations between pathogen type and the outcome ventilator-free days ( p = 0.0083) and PICU-free days (0.0238). CONCLUSIONS: This secondary analysis of the LAPSE database identified no statistically significant association of pathogen type with composite mortality and morbidity outcomes. However, pathogen type may be associated with PICU resources employed to treat sepsis organ dysfunction. Ultimately, pediatric septic shock was frequently associated with adverse patient-centered, clinically meaningful outcomes regardless of infectious disease pathogen type.

The Association of Early Corticosteroid Therapy With Clinical and Health-Related Quality of Life Outcomes in Children With Septic Shock.

OBJECTIVES: Corticosteroids are commonly used in the treatment of pediatric septic shock without clear evidence of the potential benefits or risks. This study examined the association of early corticosteroid therapy with patient-centered clinically meaningful outcomes. DESIGN: Subsequent cohort analysis of data derived from the prospective Life After Pediatric Sepsis Evaluation (LAPSE) investigation. Outcomes among patients receiving hydrocortisone or methylprednisolone on study day 0 or 1 were compared with those who did not use a propensity score-weighted analysis that controlled for age, sex, study site, and measures of first-day illness severity. SETTING: Twelve academic PICUs in the United States. PATIENTS: Children with community-acquired septic shock 1 month to 18 years old enrolled in LAPSE, 2013-2017. Exclusion criteria included a history of chronic corticosteroid administration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among children enrolled in LAPSE, 352 of 392 met analysis inclusion criteria, and 155 of 352 (44%) received early corticosteroid therapy. After weighting corticosteroid therapy administration propensity across potentially confounding baseline characteristics, differences in outcomes associated with treatment were not statistically significant (adjusted effect or odds ratio [95% CI]): vasoactive-inotropic support duration (-0.37 d [-1.47 to 0.72]; p = 0.503), short-term survival without new morbidity (1.37 [0.83-2.28]; p = 0.218), new morbidity among month-1 survivors (0.70 [0.39-1.23]; p = 0.218), and persistent severe deterioration of health-related quality of life or mortality at month 1 (0.70 [0.40-1.23]; p = 0.212). CONCLUSIONS: This study examined the association of early corticosteroid therapy with mortality and morbidity among children encountering septic shock. After adjusting for variables with the potential to confound the relationship between early corticosteroid administration and clinically meaningful end points, there was no improvement in outcomes associated with this therapy. Results from this propensity analysis provide additional justification for equipoise regarding corticosteroid therapy for pediatric septic shock and ascertain the need for a well-designed clinical trial to examine benefit/risk for this intervention.

Characterization of Inhaled Nitric Oxide Use for Cardiac Indications in Pediatric Patients.

OBJECTIVES: Characterize the use of inhaled nitric oxide (iNO) for pediatric cardiac patients and assess the relationship between patient characteristics before iNO initiation and outcomes following cardiac surgery. DESIGN: Observational cohort study. SETTING: PICU and cardiac ICUs in seven Collaborative Pediatric Critical Care Research Network hospitals. PATIENTS: Consecutive patients, less than 18 years old, mechanically ventilated before or within 24 hours of iNO initiation. iNO was started for a cardiac indication and excluded newborns with congenital diaphragmatic hernia, meconium aspiration syndrome, and persistent pulmonary hypertension, or when iNO started at an outside institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four-hundred seven patients with iNO initiation based on cardiac dysfunction. Cardiac dysfunction patients were administered iNO for a median of 4 days (2-7 d). There was significant morbidity with 51 of 407 (13%) requiring extracorporeal membrane oxygenation and 27 of 407 (7%) requiring renal replacement therapy after iNO initiation, and a 28-day mortality of 46 of 407 (11%). Of the 366 (90%) survivors, 64 of 366 patients (17%) had new morbidity as assessed by Functional Status Scale. Among the postoperative cardiac surgical group (n = 301), 37 of 301 (12%) had a superior cavopulmonary connection and nine of 301 (3%) had a Fontan procedure. Based on echocardiographic variables prior to iNO (n = 160) in the postoperative surgical group, right ventricle dysfunction was associated with 28-day and hospital mortalities (both, p < 0.001) and ventilator-free days (p = 0.003); tricuspid valve regurgitation was only associated with ventilator-free days (p < 0.001), whereas pulmonary hypertension was not associated with mortality or ventilator-free days. CONCLUSIONS: Pediatric patients in whom iNO was initiated for a cardiac indication had a high mortality rate and significant morbidity. Right ventricular dysfunction, but not the presence of pulmonary hypertension on echocardiogram, was associated with ventilator-free days and mortality.

Health Resource Use in Survivors of Pediatric Septic Shock in the United States.

OBJECTIVES: To evaluate postdischarge health resource use in pediatric survivors of septic shock and determine patient and hospitalization factors associated with health resource use. DESIGN: Secondary analyses of a multicenter prospective observational cohort study. SETTING: Twelve academic PICUs. PATIENTS: Children greater than or equal to 1 month and less than 18 years old hospitalized for community-acquired septic shock who survived to 1 year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For 308/338 patients (91%) with baseline and greater than or equal to one postdischarge survey, we evaluated readmission, emergency department (ED) visits, new medication class, and new device class use during the year after sepsis. Using negative binomial regression with bidirectional stepwise selection, we identified factors associated with each outcome. Median age was 7 years (interquartile range, 2-13), 157 (51%) had a chronic condition, and nearly all patients had insurance (private [n = 135; 44%] or government [n = 157; 51%]). During the year after sepsis, 128 patients (42%) were readmitted, 145 (47%) had an ED visit, 156 (51%) started a new medication class, and 102 (33%) instituted a new device class. Having a complex chronic condition was independently associated with readmission and ED visit. Documented infection and higher sum of Pediatric Logistic Organ Dysfunction--2 hematologic score were associated with readmission, whereas younger age and having a noncomplex chronic condition were associated with ED visit. Factors associated with new medication class use were private insurance, neurologic insult, and longer PICU stays. Factors associated with new device class use were preadmission chemotherapy or radiotherapy, presepsis Functional Status Scale score, and ventilation duration greater than or equal to 10 days. Of patients who had a new medication or device class, most had a readmission (56% and 61%) or ED visit (62% and 67%). CONCLUSIONS: Children with septic shock represent a high-risk cohort with high-resource needs after discharge. Interventions and targeted outcomes to mitigate postdischarge resource use may differ based on patients' preexisting conditions.