Pediatric allogeneic hematopoietic cell transplant (HCT) survival is limited by the development of post-transplant infections. In this overview, we discuss a clinical approach to the prompt recognition and treatment of fever and hypotension in pediatric HCT patients. Special attention is paid to individualized hemodynamic resuscitation, thorough diagnostic testing, novel anti-pathogen therapies, and the multimodal support required for recovery. We present three case vignettes that illustrate the complexities of post-HCT sepsis and highlight best practices that contribute to optimal transplant survival in children.

Objectives

Data on outcomes of children with cystic fibrosis admitted to PICUs are limited and outdated. Prior studies cite PICU mortality rates ranging from 37.5% to 100%. Given the advances made in cystic fibrosis care, we expect outcomes for these patients to have changed significantly since last studied. We provide an updated report on PICU mortality and the factors associated with death among critically ill children with cystic fibrosis.

Design

Retrospective multicenter cohort analysis utilizing data from the Virtual Pediatric Systems database.

Setting

Data were collected from 135 PICUs from January 1, 2009, to June 20, 2018.

Patients

One-thousand six-hundred thirty-three children with cystic fibrosis accounting for 2,893 PICU admissions were studied.

Interventions

None.

Measurements and main results

The primary outcome was mortality during PICU admission. Predictors included demographics, anthropometrics, diagnoses, clinical characteristics, and critical care interventions. Odds ratios of mortality were calculated in univariate and multivariable analyses to assess differences in mortality associated with predictor variables. Generalized estimating equation models were used to account for multiple admissions per patient. The overall PICU mortality rate was 6.6%. Factors associated with increased odds of mortality included hemoptysis/pulmonary hemorrhage, pneumothorax, gastrointestinal bleeding, bacterial/fungal infections, lower body mass index/malnutrition, and need for noninvasive or invasive respiratory support. Intubation/mechanical ventilation occurred in 26.4% of the 2,893 admissions and was associated with a 19.1% mortality rate. Of the nonsurvivors, 20.7% died without receiving mechanical ventilation.

Conclusions

The mortality rate during PICU admissions for patients with cystic fibrosis is lower than has been reported in prior studies, both in the overall cohort and in the subset requiring invasive mechanical ventilation. These data provide updated insight into the prognosis for cystic fibrosis patients requiring critical care.

Objectives

Over 2,500 children undergo hematopoietic stem cell transplantation in the United States each year, and up to 35% require PICU support for life-threatening complications. PICU mortality has dropped from 85% to 44%, but interpretation is confounded by significant cohort heterogeneity. Reports conflict regarding outcomes for patients with different underlying hematopoietic stem cell transplantation indications, and the burden of infectious complications for these patients has not been evaluated. We aim to describe infections, critical care interventions, and mortality for pediatric hematopoietic stem cell transplantation patients requiring PICU admission.

Design

A retrospective multicenter cohort analysis.

Setting

One hundred twelve centers in the Virtual PICU Systems database, January 1, 2009, to June 30, 2012.

Patients

A total of 1,782 admissions for patients who are 21 years old or younger with prior hematopoietic stem cell transplantation.

Interventions

None.

Measurements and main results

Pediatric Index of Mortality-2, Pediatric Risk of Mortality-3, transplant indication, infections, interventions, and mortality were recorded from admission through PICU death or discharge. Pediatric hematopoietic stem cell transplantation patients comprised 0.7% of all PICU admissions (1,782/246,346), which resulted in 16.2% mortality compared with 2.4% mortality for non-hematopoietic stem cell transplantation admissions (odds ratio, 7.8; 95% CI, 6.8-8.8; p < 0.001). Mortality for admissions with underlying hematologic malignancy (22.7%) was similar to that of admissions with primary immunodeficiency (19.4%; p = 0.41) but significantly greater than admissions with underlying nonmalignant non-primary immunodeficiency hematologic disease (15.4%; p = 0.020), metabolic disorder (8.1%; p < 0.001), or solid malignancy (5.7%; p < 0.001). Infection was documented in 45.7% of admissions with 22.2% mortality; viral and fungal mortality were 28.5% and 33.7%, respectively. Invasive positive pressure ventilation and renal replacement therapy were used in only 34.6% and 11.9% of admissions, with mortality of 42.5% and 51.9%, respectively.

Conclusions

PICU mortality for pediatric hematopoietic stem cell transplantation patients may be as low as 16.2% but higher for those receiving intubation (42.5%) or replacement therapy (51.9%). Hematologic malignancy and primary immunodeficiency had greater risk for mortality than other transplant indications. Greater understanding of other risk factors affecting mortality and the need for critical care support is needed.

Objectives

We sought to investigate how race, ethnicity, and socioeconomic status relate to tracheostomy insertion and post-tracheostomy mortality among infants with bronchopulmonary dysplasia (BPD).

Methods

The Vizient Clinical Database/Resource Manager was queried to identify infants born ≤32 weeks with BPD admitted to US hospitals from January 2012 to December 2020. Markers of socioeconomic status were linked to patient records from the Agency for Healthcare Research and Quality's Social Determinants of Health Database. Regression models were used to assess trends in annual tracheostomy insertion rate and odds of tracheostomy insertion and post-tracheostomy mortality, adjusting for sociodemographic and clinical factors.

Results

There were 40,021 ex-premature infants included in the study, 1614 (4.0%) of whom received a tracheostomy. Tracheostomy insertion increased from 2012 to 2017 (3.1%-4.1%), but decreased from 2018 to 2020 (3.3%-1.6%). Non-Hispanic Black infants demonstrated a 25% higher odds (aOR 1.25, 1.09-1.43) and Hispanic infants demonstrated a 20% lower odds (aOR 0.80, 0.65-0.96) of tracheostomy insertion compared with non-Hispanic White infants. Patients receiving public insurance had increased odds of tracheostomy insertion (aOR 1.15, 1.03-1.30), but there was no relation between other metrics of socioeconomic status and tracheostomy insertion within our cohort. In-hospital mortality among the tracheostomy-dependent was 14.1% and was not associated with sociodemographic factors.

Conclusions

Disparities in tracheostomy insertion are not accounted for by differences in socioeconomic status or the presence of additional neonatal morbidities. Post-tracheostomy mortality does not demonstrate the same relationships. Further investigation is needed to explore the source and potential mitigators of the identified disparities.

Rationale: Despite lower overall hospitalization rates for asthma in recent years, there has been an increase in the number of pediatric patients receiving intensive care management in the United States. Objectives: To investigate how the use of invasive and noninvasive mechanical ventilation for asthma has changed in the context of an evolving cohort of critically ill pediatric patients with asthma. Methods: We analyzed children admitted to intensive care units for asthma from 2009 through 2019 in the Virtual Pediatric Systems database. Regression analyses were used to evaluate how respiratory support interventions, mortality, and patient characteristics have changed over time. Odds ratios were calculated to determine how patient characteristics were associated with respiratory support needs. Stratified analyses were performed to determine how changing practice patterns may have differed between patient subgroups. Results: There were 67,614 admissions for 56,727 patients analyzed. Intubation occurred in 4.6% of admissions and decreased from 6.9% to 3.4% over time (P < 0.001), whereas noninvasive ventilation as the maximal respiratory support increased from 8.9% to 20.0% (P < 0.001). Over time, the cohort shifted to include more 2- to 6-year-olds and patients of Asian/Pacific Islander or Hispanic race/ethnicity. Although intubation decreased and noninvasive ventilation increased in all subgroups, the changes were most pronounced in the youngest patients and slightly less pronounced for obese patients. Conclusions: In pediatric asthma, use of intubation has halved, whereas use of noninvasive ventilation has more than doubled. This change in practice appears partially related to a younger patient cohort, although other factors merit exploration.

Purpose

Up to 38 % of children with cancer require pediatric intensive care unit (PICU) admission within 3 years of diagnosis, with reported PICU mortality of 13-27 % far exceeding that of the general PICU population. PICU outcomes data for individual cancer types are lacking and may help identify patients at risk for poor clinical outcomes.

Methods

We performed a retrospective multicenter analysis of 10,365 PICU admissions of cancer patients no greater than 21 years old among 112 PICUs between 1 January 2009 and 30 June 2012. We evaluated the effect of cancer type, age, gender, genetic syndrome, stem cell transplantation, PRISM3 score, infections, and critical care interventions on PICU mortality.

Results

After excluding scheduled perioperative admissions, cancer patients represented 4.2 % of all PICU admissions (10,365/246,346), had overall mortality of 6.8 % (708/10,365) vs. 2.4 % (5,485/230,548) in the general PICU population (RR = 2.9, 95 % CI 2.7-3.1, p < 0.001), and accounted for 11.4 % of all PICU deaths (708/6,215). Hematologic cancer patients had greater median PRISM3 score (8 vs 2, p < 0.001), rates of sepsis (27 vs 9 %, RR = 2.9, 95 % CI 2.6-3.1, p < 0.001), and mortality (9.6 vs 4.5 %, RR = 2.1, 95 % CI 1.8-2.5, p < 0.001) compared to solid cancer patients. Among hematologic cancer patients, stem cell transplantation, diagnosis of acute myeloid leukemia, PRISM3 score, and infection were all independently associated with PICU mortality.

Conclusions

Children with cancer account for 4.2 % of PICU admissions and 11.4 % of PICU deaths. Hematologic cancer patients have significantly higher admission illness severity, rates of infections, and PICU mortality than solid cancer patients. These data may be useful in risk stratification for closer monitoring and patient counseling.

Preparation of high-quality sequencing libraries is a costly and time-consuming component of metagenomic next generation sequencing (mNGS). While the overall cost of sequencing has dropped significantly over recent years, the reagents needed to prepare sequencing samples are likely to become the dominant expense in the process. Furthermore, libraries prepared by hand are subject to human variability and needless waste due to limitations of manual pipetting volumes. Reduction of reaction volumes, combined with sub-microliter automated dispensing of reagents without consumable pipette tips, has the potential to provide significant advantages. Here, we describe the integration of several instruments, including the Labcyte Echo 525 acoustic liquid handler and the iSeq and NovaSeq Illumina sequencing platforms, to miniaturize and automate mNGS library preparation, significantly reducing the cost and the time required to prepare samples. Through the use of External RNA Controls Consortium (ERCC) spike-in RNAs, we demonstrated the fidelity of the miniaturized preparation to be equivalent to full volume reactions. Furthermore, detection of viral and microbial species from cell culture and patient samples was also maintained in the miniaturized libraries. For 384-well mNGS library preparations, we achieved cost savings of over 80% in materials and reagents alone, and reduced preparation time by 90% compared to manual approaches, without compromising quality or representation within the library.

Objectives

In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes.

Design

Multicenter prospective observational study.

Setting

We enrolled patients from five academic PICUs between 2008 and 2015.

Patients

Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome.

Interventions

Eight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin.

Measurements and main results

We measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70-0.83] vs 0.70 [0.62-0.77]; p = 0.042).

Conclusions

In pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.

Objectives

As acute kidney injury and elevated cumulative fluid balance commonly co-occur in pediatric acute respiratory distress syndrome, we aimed to identify risk factors for their development and evaluate their independent relationships with mortality. We hypothesized that acute kidney injury and elevated cumulative fluid balance would be associated with markers of inflammation and that children with elevated cumulative fluid balance and concomitant acute kidney injury would have worse outcomes than other children.

Design

Prospective observational study using the pediatric Risk, Injury, Failure, Loss, End-Stage acute kidney injury classification.

Setting

Five academic PICUs.

Patients

Two-hundred sixty patients 1 month to 18 years old meeting the Berlin definition of acute respiratory distress syndrome between 2008 and 2014.

Interventions

None.

Measurements and results

PICU mortality was 13% (34/260). Relative to survivors, nonsurvivors had greater cumulative fluid balance on day 3 of acute respiratory distress syndrome (+90.1 mL/kg; interquartile range 26.6-161.7 vs +44.9 mL/kg; interquartile range 10.0-111.3; p = 0.008) and also had higher prevalence of acute kidney injury on day 3 of acute respiratory distress syndrome (50% vs 23%; p = 0.001). On stratified analysis, greater cumulative fluid balance on day 3 of acute respiratory distress syndrome was associated with mortality among patients with concomitant acute kidney injury (+111.5 mL/kg for nonsurvivors; interquartile range 82.6-236.8 vs +58.5 mL/kg for survivors; interquartile range 0.9-176.2; p = 0.041) but not among patients without acute kidney injury (p = 0.308). The presence of acute kidney injury on acute respiratory distress syndrome day 3 was associated with mortality among patients with positive cumulative fluid balance (29.1% vs 10.4% mortality; p = 0.001) but not among patients with even or negative cumulative fluid balance (p = 0.430). Day 1 plasma interleukin-6 levels were associated with the development of day 3 positive cumulative fluid balance, day 3 acute kidney injury, and PICU mortality and the association between elevated day 1 interleukin-6 and PICU mortality was partially mediated by the interval development of day 3 positive cumulative fluid balance and day 3 acute kidney injury (p < 0.001).

Conclusions

In pediatric acute respiratory distress syndrome, elevated cumulative fluid balance on day 3 of acute respiratory distress syndrome is associated with mortality specifically in patients with concomitant acute kidney injury. Plasma interleukin-6 levels are associated with the development of positive cumulative fluid balance and acute kidney injury, suggesting a potential mechanism by which inflammation might predispose to mortality.

The number of pediatric hematopoietic cell transplant (HCT) patients who survive pediatric intensive care unit (PICU) admission is increasing, yet little is known about their functional morbidity after PICU discharge. We hypothesized that relative to control subjects, pediatric HCT patients who survive PICU admission would have greater rates of new functional morbidity at the time of PICU discharge and only some of these patients would return to their functional baseline by the end of the hospitalization. We performed a retrospective cohort study with secondary data analysis of the Trichotomous Outcomes in Pediatric Critical Care dataset. The pediatric HCT cohort was identified by querying International Classification of Diseases, 9th edition, diagnostic codes. A control group consisted of previously healthy patients matched 4:1 on age, sex, and illness severity, as estimated by the Pediatric Risk of Mortality (PRISM) score. We benchmarked our findings by comparing with a previously healthy group of children with lower respiratory tract infections. Functional impairment was measured by the Functional Status Scale, wherein new morbidity was defined as an increase of ≥3 points relative to the prehospital baseline. Relative to matched control subjects, HCT patients had similar admission PRISM scores (P = .516) but greater PICU mortality (12.9% [11/85] versus 6.2% [21/340], P = .035). However, among those who survived to PICU discharge, HCT patients had similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 17.2% [55/319], P = .622) and similar rates of resolution of new morbidity by hospital discharge (54.5% [6/11] versus 60.0% [33/55], P = .737). Relative to the comparison group with lower respiratory tract infections, HCT patients had both greater admission PRISM scores (P < .001) and greater PICU mortality (12.9% [11/85] versus 1.6% [5/308], P < .001). However, among those who survived to PICU discharge, HCT patients again displayed similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 22.1% [67/303], P = .168) as well as resolution of new morbidity by hospital discharge (54.5% [6/11] versus 71.6% [48/67], P = .299). For pediatric HCT patients PICU survival with new functional morbidity is as prevalent an outcome as PICU mortality. Although pediatric HCT patients have greater PICU mortality than age-, sex-, and PRISM-matched control subjects, they have similar rates of new functional morbidity at PICU discharge and similar resolution of new functional morbidity at hospital discharge. Future interventions focused on improving functional status in pediatric HCT survivors of critical illness are warranted.