Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Child Opportunity Index and Pediatric Intensive Care Outcomes: A Multicenter Retrospective Study in the United States.

OBJECTIVES: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS). DESIGN: Retrospective cohort study. SETTING: Fifteen PICUs in the United States. PATIENTS: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance. CONCLUSIONS: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood.

Post-operative dysnatremia is associated with adverse early outcomes after surgery for congenital heart disease.

BACKGROUND: Dysnatremia is a common disorder in critically ill surgical children. The study's aim is to determine the prevalence of dysnatremia and its association with outcomes after surgery for congenital heart disease (CHD). METHODS: This is a single-center retrospective cohort study of children <18 years of age undergoing surgery for CHD between January 2012 and December 2014. Multivariable logistic regression analysis was used to evaluate the relationship between dysnatremia and outcomes during the perioperative period. A total of 1345 encounters met the inclusion criteria. RESULTS: The prevalence of pre- and post-operative dysnatremia were 10.2% and 47.1%, respectively. Hyponatremia occurred in 19.1%, hypernatremia in 25.6%. Hypernatremia at 24, 48, and 72 h post-operative was associated with increased hospital mortality (odds ratios (OR) [95% confidence intervals (CI)] 3.08 [1.16-8.17], p = 0.024; 4.35 [1.58-12], p = 0.0045; 4.14 [1.32-12.97], p = 0.0148, respectively. Hypernatremia was associated with adverse neurological events 3.39 [1.12-10.23], p = 0.0302 at 48 h post-operative. Hyponatremia was not associated with any adverse outcome in our secondary analysis. CONCLUSIONS: Post-operative dysnatremia is a common finding in this heterogeneous cohort of pediatric cardiac-surgical patients. Hypernatremia was more prevalent than hyponatremia and was associated with adverse early post-operative outcomes. IMPACT: Our study has shown that dysnatremia was highly prevalent in children after congenital heart surgery with hypernatremia associated with adverse outcomes including mortality. It is important to understand fluid and sodium regulation in the post-operative period in children with congenital heart disease to better address fluid overload and associated electrolyte imbalances and acute kidney injury. While clinicians are generally very aware of the importance of hyponatremia in critically ill children, similar attention should be given to hypernatremia in this population.

The use of tracheostomy to support critically ill children receiving orthotopic liver transplantation: a single-center experience.

BACKGROUND: Children with end-stage liver disease and multi-organ failure, previously considered as poor surgical candidates, can now benefit from liver transplantation (LT). They often need prolonged mechanical ventilation (MV) post-LT and may need tracheostomy to advance care. Data on tracheostomy after pediatric LT are lacking. METHOD: Retrospective chart review of children who required tracheostomy in the peri-LT period in a large, freestanding quaternary children's hospital from 2014 to 2019. RESULTS: Out of 205 total orthotopic LTs performed in 200 children, 18 (9%) required tracheostomy in the peri-transplant period: 4 (2%) pre-LT and 14 (7%) post-LT. Among those 14 needing tracheostomy post-LT, median age was 9 months [IQR = 7, 14] at LT and 10 months [9, 17] at tracheostomy. Nine (64%) were infants and 12 (85%) were cirrhotic at the time of LT. Seven (50%) were intubated before LT. Median MV days prior to LT was 23 [7, 36]. Eight (57%) patients received perioperative continuous renal replacement therapy (CRRT). The median MV days from LT to tracheostomy was 46 [33, 56]; total MV days from initial intubation to tracheostomy was 57 [37, 66]. Four (28%) children died, of which 3 (21%) died within 1 year of transplant. Total ICU and hospital length of stay were 92 days [I72, 126] and 177 days [115, 212] respectively. Among survivors, 3/10 (30%) required MV at home and 8/10 (80%) were successfully decannulated at 400 median days [283, 584]. CONCLUSION: Tracheostomy though rare after LT remains a feasible option to support and rehabilitate critically ill children who need prolonged MV in the peri-LT period.

Clinical Consequences of Cardiomyopathy in Children With Biliary Atresia Requiring Liver Transplantation.

Cirrhotic cardiomyopathy (CCM), a comorbidity of end-stage cirrhotic liver disease, remains uncharacterized in children, largely because of a lack of an established pediatric definition. The aim of this retrospective cohort analysis is to derive objective two-dimensional echocardiographic (2DE) criteria to define CCM associated with biliary atresia (BA), or BA-CCM, and correlate presence of BA-CCM with liver transplant (LT) outcomes in this population. Using receiver operating characteristic (ROC) curve analysis, optimal cut-off values for left ventricular (LV) geometrical parameters that were highly sensitive and specific for the primary outcomes: A composite of serious adverse events (CSAE) and peritransplant death were determined. These results were used to propose a working definition for BA-CCM: (1) LV mass index (LVMI) ≥95 g/m2.7 or (2) relative wall thickness of LV ≥0.42. Applying these criteria, BA-CCM was found in 34 of 69 (49%) patients with BA listed for LT and was associated with increased multiorgan dysfunction, mechanical and vasopressor support, and longer intensive care unit (ICU) and hospital stays. BA-CCM was present in all 4 waitlist deaths, 7 posttransplant deaths, and 20 patients with a CSAE (P < 0.01). On multivariable regression analysis, BA-CCM remained independently associated with both death and a CSAE (P < 0.01). Utilizing ROC analysis, LVMI was found to be a stronger predictor for adverse outcomes compared with current well-established markers, including Pediatric End-Stage Liver Disease (PELD) score. Conclusion: BA-CCM is highly sensitive and specific for morbidity and mortality in children with BA listed for LT. 2DE screening for BA-CCM may provide pertinent clinical information for prioritization and optimal peritransplant management of these children.

Profile of Fluid Exposure and Recognition of Fluid Overload in Critically Ill Children.

OBJECTIVES: Fluid overload is common in the PICU and has been associated with increased morbidity and mortality. It remains unclear whether fluid overload is a surrogate marker for severity of illness and need for increased support, an iatrogenic modifiable risk factor, or a sign of oliguria. The proportions of various fluid intake contributing to fluid overload and its recognition have not been adequately examined. We aimed to: 1) describe the types and amounts of fluid exposure in the PICU and 2) identify the clinicians' recognition of fluid overload. SETTING: Noncardiac PICU in a quaternary care hospital. PATIENTS: Pediatric patients admitted for more than 24 hours. DESIGN: Prospective observational study over 28 days. INTERVENTIONS: Data were collected on the amount and type of fluid exposure-resuscitative boluses, blood products, enteral intake, parenteral nutrition (total parenteral nutrition), or modifiable fluids (IV fluids and medications) indexed to the patients' admission body surface area on days 1 and 3. Charts of patients admitted for 3 days who developed 15% fluid overload were reviewed to assess clinicians' recognition of fluid overload. MEASUREMENTS AND MAIN RESULTS: One hundred two patients were included. Day 1 median fluid exposure was 2,318 mL/m (1,831-3,037 mL/m; 1,646 mL/m [1,296-2,086 mL/m] modifiable fluids). Forty-seven patients (46%) received fluid boluses, and 16 (16%) received blood products. Day 3 median fluid exposure was 2,233 mL/m (1,904-2,556 mL/m; 750 mL/m [375-1,816 mL/m] modifiable fluids). Of the 54 patients, one patient (1.9%) received a fluid bolus and two (3.7%) received blood products. In our cohort, 47 of 54 (87%) had fluid exposure greater than 1,600 mL/m on day 3. Fluid overload was not recognized by the clinicians in 30% of the patients who developed more than 15% fluid overload. CONCLUSIONS: Although resuscitation fluids contributed more to fluid exposure on day 1 compared with day 3, fluid exposure frequently exceeded maintenance requirements on day 3. Fluid overload was not always recognized by PICU practitioners. Further studies to correlate modifiable fluid exposure to fluid overload and explore modifiable practice improvement opportunities are needed.

Comparing Vasoactive-Inotropic Score Reporting Strategies in the PICU Relative to Mortality Risk.

OBJECTIVES: High Vasoactive-Inotropic Scores have demonstrated association with poor outcomes in pediatric cardiac ICUs and are being calculated more frequently in studies of critically ill noncardiac patients. Available studies differ in their approach to assigning Vasoactive-Inotropic Scores, making direct comparisons difficult. The goal of this investigation is to compare multiple approaches to Vasoactive-Inotropic Score assignment to determine their strength of association with mortality in a general pediatric intensive care population. In doing so, we aim to help validate the use of the Vasoactive-Inotropic Score in noncardiac patients and to help inform future studies of the relative strength of available approaches in assigning this score. DESIGN: Retrospective chart review. SETTING: PICU at an academic freestanding children's hospital. PATIENTS: Two-thousand seven-hundred fifty-two consecutive patients admitted over a 17-month time period were screened for receiving inotrope or vasopressor therapies regardless of disease process. Four-hundred seventy-four patients met inclusion criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For each patient treated with continuous infusions of vasoactive medications, a Vasoactive-Inotropic Score was calculated (and then recalculated) every time they had a documented dose change. Multiple strategies were evaluated to generate receiver operating characteristic curves in relation to mortality. Area under the curve was greatest when evaluating the maximum Vasoactive-Inotropic Score (Max Any) during the initial treatment course (0.788) with an increasing relative risk as the score increased. The Vasoactive-Inotropic Score at 48 hours after treatment initiation had next highest area under the curve (0.736). Primary diagnosis categories were also analyzed, and area under the curve was greatest for the cardiovascular group (0.879). CONCLUSIONS: Increasing Vasoactive-Inotropic Scores for patients in the PICU are associated with mortality risk. The scoring strategy used can influence the strength of the association, as can the primary diagnosis category.

Risk Factors for Ventilator-Associated Events in a PICU.

OBJECTIVE: The term ventilator-associated events includes ventilator-associated condition, infection-related ventilator-associated complication, and ventilator-associated pneumonia. We sought to identify potential new risk factors for ventilator-associated condition and infection-related ventilator-associated complication in the PICU population. DESIGN: Matched case control study. SETTING: Children's hospital at a tertiary care academic medical center. PATIENTS: During the study period, 606 patients were admitted to PICU and ventilated more than 48 hours; 70 children met ventilator-associated condition criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the definition for ventilator-associated condition (i.e., a sustained increase in ventilator settings after a period of stable or decreasing support) to our database. Within ventilator-associated condition cases, 40 cases were infection-related ventilator-associated complication and 30 cases were noninfectious-related ventilator-associated condition. We identified 140 controls and matched to ventilator-associated condition cases with regard to age, immunocompromised status, and ventilator days to event. Patients with ventilator-associated condition had longer ICU stay versus controls; 24 days median (12-43 interquartile range) versus 7 days (4-14); (p < 0.01), respectively, and longer duration of ventilatory support 17 days (10-32) versus 6 days (3-10); p < 0.01, respectively. Mortality was 22.8% in the ventilator-associated condition versus 9% in the control group (p < 0.01). A multivariate regression analysis adjusted for Pediatric Index of Mortality 2 identified mean peak inspiratory pressure and acute kidney injury to be associated with ventilator-associated condition (odds ratio, 1.12 [95% CI, 1.02-1.22] and odds ratio, 2.85 [1.43-5.66], respectively). Acute kidney injury and neuromuscular blockade in a multivariate regression analysis adjusted for Pediatric Index of Mortality 2 were associated with infection-related ventilator-associated complication (odds ratio, 2.36 [1.03-5.40] and 3.19 [1.17-8.68], respectively). CONCLUSIONS: There is an association between ventilator-associated condition and infection-related ventilator-associated complication in critically ill children with acute kidney injury, ventilatory support, and neuromuscular blockade. Attention should be given by clinical practitioners to recognize these modifiable risk factors and to implement strategies to decrease the prevalence of ventilator-associated events.

Hepatobiliary Dysfunction and Disseminated Intravascular Coagulation Increase Risk of Mortality in Pediatric Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis poses significant challenges due to limited tools to guide clinical decisions in a population at high risk of death. We sought to assess whether disseminated intravascular coagulation and hepatobiliary dysfunction, significant comorbidities seen in critical care settings, would identify hemophagocytic lymphohistiocytosis patients with increased risk of mortality. DESIGN: Retrospective chart review. SETTING: Single-center PICU. PATIENTS: All patients admitted to a tertiary care children's hospital diagnosed with hemophagocytic lymphohistiocytosis from 2005 to 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-three patients were diagnosed with hemophagocytic lymphohistiocytosis with median age of 61 months. The 5-year overall survival was 51% (22/43). Univariate analyses revealed ferritin levels greater than 10,000 (ng/mL), international normalized ratio greater than 1.5, or platelet counts less than 100,000/µL at initiation of dexamethasone were individually associated with mortality. Development of disseminated intravascular coagulation, hepatobiliary dysfunction, or both increased the likelihood of death in hemophagocytic lymphohistiocytosis patients (relative risk; 95% CI) (6; 1.4-34; p < 0.05), (4.1; 1.8-10; p < 0.05), and (7.5; 1.8-42; p < 0.05). Of 12 autopsies performed, 75% had at least one active infection, 66% had chronic lymphopenia, 50% had lymphocyte depletion in the spleen, thymus, or bone marrow, 42% had evidence of microvascular thrombosis, and 92% had evidence of hepatocellular injury. CONCLUSIONS: Hemophagocytic lymphohistiocytosis continues to have high mortality with hemophagocytic lymphohistiocytosis-1994/2004 (dexamethasone/etoposide), the current standard of care for all children with hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis patients who developed disseminated intravascular coagulation, hepatobiliary dysfunction, or both had higher risk of death with mortalities of 60%, 77%, and 77%, respectively. Phenotypic classifications are urgently needed to guide individualized treatment strategies to improve outcomes for children with hemophagocytic lymphohistiocytosis.

The Use of Nesiritide in Children With Congenital Heart Disease.

OBJECTIVE: We evaluated the use of nesiritide in children with critical congenital heart disease, pulmonary congestion, and inadequate urine output despite conventional diuretic therapy. DESIGN: We conducted a retrospective analysis of 26 consecutive patients, comprising 37 infusions occurring during separate hospitalizations. Hemodynamic variables, urine output, and serum creatinine levels were monitored prior to and throughout the duration of therapy with nesiritide. In addition, the stage of acute kidney injury was determined prior to and throughout the duration of the therapy using a standardized definition of acute kidney injury-The Kidney Disease: Improving Global Outcomes criteria. SETTING: Cardiac ICU. PATIENTS: Pediatric patients with critical congenital heart disease, pulmonary congestion, and inadequate urinary output despite diuretic therapy. INTERVENTION: Nesiritide infusion. MEASUREMENTS AND MAIN RESULTS: The use of nesiritide was associated with a significant decrease in the central venous pressure and heart rate with a trend toward a significant increase in urine output. During the course of therapy with nesiritide, the serum creatinine and stage of acute kidney injury decreased significantly. The decrease in stage of acute kidney injury became significant by day 4 (p = 0.006) and became more significant with time (last day of therapy compared with baseline; p < 0.001). During 12 of the 37 infusions, the stage of acute kidney injury decreased by two or more (p < 0.001). CONCLUSIONS: Nesiritide had a favorable impact on hemodynamics and urine output in children with critical congenital heart disease and pulmonary congestion, and there was no worsening of renal function.

Fluid Overload and Kidney Injury Score: A Multidimensional Real-Time Assessment of Renal Disease Burden in the Critically Ill Patient.

OBJECTIVE: Interruptive acute kidney injury alerts are reported to decrease acute kidney injury-related mortality in adults. Critically ill children have multiple acute kidney injury risk factors; although recognition has improved due to standardized definitions, subtle changes in serum creatinine make acute kidney injury recognition challenging. Age and body habitus variability prevent a uniform maximum threshold of creatinine. Exposure of nephrotoxic medications is common but not accounted for in kidney injury scores. Current severity of illness measures do not include fluid overload, a well-described mortality risk factor. We hypothesized that a multidimensional measure of renal status would better characterize renal severity of illness while maintaining or improving on correlation measures with adverse outcomes, when compared with traditional acute kidney injury staging. DESIGN: A novel, real-time, multidimensional, renal status measure, combining acute kidney injury, fluid overload greater than or equal to 15%, and nephrotoxin exposure, was developed (Fluid Overload Kidney Injury Score) and prospectively applied to all patient encounters. Peak Fluid Overload Kidney Injury Score values prior to discharge or death were used to measure correlation with outcomes. SETTING: Quarternary PICU of a freestanding children's hospital. PATIENTS: All patients admitted over 18 months. INTERVENTION: None. RESULTS: Peak Fluid Overload Kidney Injury Score ranged between 0 and 14 in 2,830 PICU patients (median age, 5.5 yr; interquartile range, 1.3-12.9; 55% male), 66% of patients had Fluid Overload Kidney Injury Score greater than or equal to 1. Fluid Overload Kidney Injury Score was independently associated with PICU mortality and PICU and hospital length of stay when controlled for age, Pediatric Risk of Mortality-3, ventilator, pressor, and renal replacement therapy use (p = 0.047). Mortality increased from 1.5% in Fluid Overload Kidney Injury Score 0 to 40% in Fluid Overload Kidney Injury Score 8+. When urine output points were excluded, Fluid Overload Kidney Injury Score was more strongly correlated with mortality than fluid overload or acute kidney injury definitions alone. CONCLUSION: A multidimensional score of renal disease burden was significantly associated with adverse PICU outcomes. Further studies will evaluate Fluid Overload Kidney Injury Score as a warning and decision support tool to impact patient-centered outcomes.

The use of nesiritide in patients with critical cardiac disease.

OBJECTIVE: We evaluated the use of nesiritide in children with critical CHD, pulmonary congestion, and inadequate urine output despite undergoing conventional diuretic therapy. DESIGN: We conducted a retrospective analysis of 11 patients with critical CHD, comprising 18 infusions, each of which occurred during separate hospitalisations. Haemodynamic parameters were assessed, and the stage of acute kidney injury was determined before and throughout the duration of therapy using a standardised definition of acute kidney injury - The Kidney Disease: Improving Global Outcomes criteria. Patients Children with critical CHD, pulmonary congestion, and inadequate urinary output despite undergoing diuretic therapy were included. Measurements and main results The use of nesiritide was associated with a significant decrease in the maximum and minimum heart rate values and with a trend towards a significant decrease in maximum systolic blood pressure and maximum and minimum central venous pressures. Urine output increased but was not significant. Serum creatinine levels decreased significantly during the course of therapy (-0.26 mg/dl [-0.50, 0.0], p=0.02), and the number of patients who experienced a decrease in the stage of acute kidney injury of 2 or more - where a change in the stage of acute kidney disease of 2 or more was possible, that is, baseline stage >1 - was highly significant (five of 12 patients, 42%, p<0.001). CONCLUSIONS: Nesiritide had a favourable impact on haemodynamics, and its use was not associated with deterioration of renal function in patients with critical CHD.

The Centers for Disease Control and Prevention's New Definitions for Complications of Mechanical Ventilation Shift the Focus of Quality Surveillance and Predict Clinical Outcomes in a PICU.

OBJECTIVES: The Centers for Disease Control and Prevention shifted the focus of surveillance paradigm for adult patients receiving mechanical ventilation, moving from the current standard of ventilator-associated pneumonia to broader complications. The surveillance definitions were designed to enable objective measures and efficient processes, so as to facilitate quality improvement initiatives and enhance standardized benchmark comparisons. We evaluated the surveillance definitions in term of their ability to predict clinical outcomes and ease of surveillance in a PICU. DESIGN: Retrospective cohort study. SETTING: A PICU at a university-affiliated children's hospital. PATIENTS: Eight hundred thirty-six patients receiving mechanical ventilation over 1-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the definition for ventilator-associated condition (i.e., a sustained increase in ventilator setting after a period of stable or decreasing support) to our database. Of total 606 patients, 14.5% had ventilator-associated condition (20.9/1,000 ventilator days) and 8.1% had an infection-related ventilator-associated condition (12.9/1,000 ventilator days). The patients with infection-related ventilator-associated condition were classified into probable pneumonia (55%), possible pneumonia (28.6%), and undetermined infection (16.3%). A large portion of patients with ventilator-associated condition (44%) had other noninfectious etiologies (e.g., atelectasis, pulmonary edema, and shock). Patients who developed ventilator-associated condition had significantly longer ventilatory, ICU, and hospital days compared with those who did not. The ventilator-associated condition group had increased hospital mortality compared with the non-ventilator-associated condition group (19.3% vs 6.9%; p=0.0007). Multivariate regression analysis identified ventilator-associated condition as one of the predictors of hospital mortality with an adjusted odds ratio of 2.14 (95% CI, 1.03-4.42). Risk factors for developing a ventilator-associated condition included immunocompromised status (odds ratio, 2.90; 95% CI, 1.57-5.33), tracheostomy dependence (odds ratio, 2.78; 95% CI, 1.40-5.51), and chronic respiratory disease (odds ratio, 1.85; 95% CI, 1.03-3.3). CONCLUSIONS: The definitions for the various ventilator-associated conditions are good predictors of outcomes in children and adults and are amenable to automated surveillance. Based on the study findings, we suggest consideration for shifting the focus of surveillance for ventilator-associated events from only pneumonia to a broader range of complications.

Resuscitation Bundle in Pediatric Shock Decreases Acute Kidney Injury and Improves Outcomes.

OBJECTIVE: To investigate the impact of an early emergency department (ED) protocol-driven resuscitation (septic shock protocol [SSP]) on the incidence of acute kidney injury (AKI). STUDY DESIGN: This was a retrospective pediatric cohort with clinical sepsis admitted to the pediatric intensive care unit (PICU) from the ED before (2009, PRE) and after (2010, POST) implementation of the SSP. AKI was defined by pRIFLE (pediatric version of the Risk of renal dysfunction; Injury to kidney; Failure of kidney function; Loss of kidney function, End-stage renal disease creatinine criteria). RESULTS: A total of 202 patients (PRE, n = 98; POST, n = 104) were included (53% male, mean age 7.7 ± 5.6 years, mean Pediatric Logistic Organ Dysfunction [PELOD] 8.9 ± 12.7, mean Pediatric Risk of Mortality score 5.3 ± 13.9). There were no differences in demographics or illness severity between the PRE and POST groups. POST was associated with decreased AKI (54% vs 29%, P < .001), renal-replacement therapy (4 vs 0, P = .04), PICU, and hospital lengths of stay (LOS) (1.9 ± 2.3 vs 4.5 ± 7.6, P < .01; 6.3 ± 5.1 vs 15.3 ± 16.9, P < .001, respectively), and mortality (10% vs 3%, P = .037). The SSP was independently associated with decreased AKI when we controlled for age, sex, and PELOD (OR 0.27, CI 0.13-0.56). In multivariate analyses, the SSP was independently associated with shorter PICU and hospital LOS when we controlled for AKI and PELOD (P = .02, P < .001, respectively). CONCLUSION: A protocol-driven implementation of a resuscitation bundle in the pediatric ED decreased AKI and need for renal-replacement therapy, as well as PICU and hospital LOS and mortality.

Using Time Series Analysis to Predict Cardiac Arrest in a PICU.

OBJECTIVES: To build and test cardiac arrest prediction models in a PICU, using time series analysis as input, and to measure changes in prediction accuracy attributable to different classes of time series data. DESIGN: Retrospective cohort study. SETTING: Thirty-one bed academic PICU that provides care for medical and general surgical (not congenital heart surgery) patients. SUBJECTS: Patients experiencing a cardiac arrest in the PICU and requiring external cardiac massage for at least 2 minutes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred three cases of cardiac arrest and 109 control cases were used to prepare a baseline dataset that consisted of 1,025 variables in four data classes: multivariate, raw time series, clinical calculations, and time series trend analysis. We trained 20 arrest prediction models using a matrix of five feature sets (combinations of data classes) with four modeling algorithms: linear regression, decision tree, neural network, and support vector machine. The reference model (multivariate data with regression algorithm) had an accuracy of 78% and 87% area under the receiver operating characteristic curve. The best model (multivariate + trend analysis data with support vector machine algorithm) had an accuracy of 94% and 98% area under the receiver operating characteristic curve. CONCLUSIONS: Cardiac arrest predictions based on a traditional model built with multivariate data and a regression algorithm misclassified cases 3.7 times more frequently than predictions that included time series trend analysis and built with a support vector machine algorithm. Although the final model lacks the specificity necessary for clinical application, we have demonstrated how information from time series data can be used to increase the accuracy of clinical prediction models.

Twilight length alters growth and flowering time in Arabidopsis via LHY/CCA1.

Decades of research have uncovered how plants respond to two environmental variables that change across latitudes and over seasons: photoperiod and temperature. However, a third such variable, twilight length, has so far gone unstudied. Here, using controlled growth setups, we show that the duration of twilight affects growth and flowering time via the LHY/CCA1 clock genes in the model plant Arabidopsis. Using a series of progressively truncated no-twilight photoperiods, we also found that plants are more sensitive to twilight length compared to equivalent changes in solely photoperiods. Transcriptome and proteome analyses showed that twilight length affects reactive oxygen species metabolism, photosynthesis, and carbon metabolism. Genetic analyses suggested a twilight sensing pathway from the photoreceptors PHY E, PHY B, PHY D, and CRY2 through LHY/CCA1 to flowering modulation through the GI-FT pathway. Overall, our findings call for more nuanced models of day-length perception in plants and posit that twilight is an important determinant of plant growth and development.

Machine learning classification of plant genotypes grown under different light conditions through the integration of multi-scale time-series data.

In order to mitigate the effects of a changing climate, agriculture requires more effective evaluation, selection, and production of crop cultivars in order to accelerate genotype-to-phenotype connections and the selection of beneficial traits. Critically, plant growth and development are highly dependent on sunlight, with light energy providing plants with the energy required to photosynthesize as well as a means to directly intersect with the environment in order to develop. In plant analyses, machine learning and deep learning techniques have a proven ability to learn plant growth patterns, including detection of disease, plant stress, and growth using a variety of image data. To date, however, studies have not assessed machine learning and deep learning algorithms for their ability to differentiate a large cohort of genotypes grown under several growth conditions using time-series data automatically acquired across multiple scales (daily and developmentally). Here, we extensively evaluate a wide range of machine learning and deep learning algorithms for their ability to differentiate 17 well-characterized photoreceptor deficient genotypes differing in their light detection capabilities grown under several different light conditions. Using algorithm performance measurements of precision, recall, F1-Score, and accuracy, we find that Suport Vector Machine (SVM) maintains the greatest classification accuracy, while a combined ConvLSTM2D deep learning model produces the best genotype classification results across the different growth conditions. Our successful integration of time-series growth data across multiple scales, genotypes and growth conditions sets a new foundational baseline from which more complex plant science traits can be assessed for genotype-to-phenotype connections.

Elevated bile acids are associated with left ventricular structural changes in biliary atresia.

BACKGROUND: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood. METHODS: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5. RESULTS: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry. CONCLUSION: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

Cardiac structural and functional alterations in infants and children with biliary atresia, listed for liver transplantation.

BACKGROUND & AIMS: Cirrhotic liver diseases are associated with abnormalities in cardiac geometry and function in adults (cirrhotic cardiomyopathy) but rarely explored in cirrhotic infants or children. We proposed that features of cirrhotic cardiomyopathy are present in infants with cirrhosis due to biliary atresia (BA) as early as the time of evaluation for liver transplant and will correlate with mortality and postoperative morbidity. METHODS: Two-dimensional echocardiography (2DE) of infants with BA (n=40; median age, 8 months), listed for transplantation at the Texas Children's Hospital from 2004 to 2010, were reviewed and compared with age- and sex-matched infants without cardiac or liver disease (controls). Length of stay and correlation with 2DE results were assessed. RESULTS: Compared with controls, children with BA had significant increases in multiple 2DE parameters, notably left ventricle wall thickness (23% increase), left ventricular (LV) mass indexed to body surface area (51% increase), and LV shortening fraction (8% increase). Overall, features of cirrhotic cardiomyopathy were observed in most infants (29/40; 72%); 17 had hyperdynamic contractility, and 24 had altered LV geometry. After liver transplantation (33), infants with abnormal 2DE results had longer stays in the intensive care unit (median, 6 vs 4 days) and the hospital (21 vs 11 days) compared with infants who had normal 2DE reports. On univariate analysis, the length of hospital stay correlated with LV mass index. CONCLUSIONS: Cardiomyopathy is a prevalent condition in infants with end-stage cirrhotic liver disease due to BA (>70%). This underrecognized condition likely contributes to the prolongation of posttransplant hospitalization.