OBJECTIVES:A companion article reports the trajectory of long-term mortality and significant health-related quality of life disability among children encountering septic shock. In this article, the ...investigators examine critical illness factors associated with these adverse outcomes.
DESIGN:Prospective, cohort-outcome study, conducted 2013–2017.
SETTING:Twelve United States academic PICUs.
PATIENTS:Critically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support.
INTERVENTIONS:Illness severity, organ dysfunction, and resource utilization data were collected during PICU admission. Change from baseline health-related quality of life at the month 3 follow-up was assessed by parent proxy-report employing the Pediatric Quality of Life Inventory or the Stein-Jessop Functional Status Scale.
MEASUREMENTS AND MAIN RESULTS:In univariable modeling, critical illness variables associated with death and/or persistent, serious health-related quality of life deterioration were candidates for multivariable modeling using Bayesian information criterion. The most clinically relevant multivariable models were selected among models with near-optimal statistical fit. Three months following septic shock, 346 of 389 subjects (88.9%) were alive and 43 of 389 had died (11.1%); 203 of 389 (52.2%) had completed paired health-related quality of life surveys. Pediatric Risk of Mortality, cumulative Pediatric Logistic Organ Dysfunction scores, PICU and hospital durations of stay, maximum and cumulative vasoactive-inotropic scores, duration of mechanical ventilation, need for renal replacement therapy, extracorporeal life support or cardiopulmonary resuscitation, and appearance of pathologic neurologic signs were associated with adverse outcomes in univariable models. In multivariable regression analysis (odds ratio 95% CI), summation of daily Pediatric Logistic Organ Dysfunction scores, 1.01/per point (1.01–1.02), p < 0.001; highest vasoactive-inotropic score, 1.02/per point (1.00–1.04), p = 0.003; and any acute pathologic neurologic sign/event, 5.04 (2.15–12.01), p < 0.001 were independently associated with death or persistent, serious deterioration of health-related quality of life at month 3.
CONCLUSIONS AND RELEVANCE:Biologically plausible factors related to sepsis-associated critical illness organ dysfunction and its treatment were associated with poor outcomes at month 3 follow-up among children encountering septic shock.
OBJECTIVE:The objective was to compare the resolution of organ dysfunction, 28-day mortality, and biochemical markers in children with thrombocytopenia-associated multiple organ failure who received ...therapeutic plasma exchange versus no therapeutic plasma exchange.
DESIGN:Observational longitudinal cohort study.
SETTING:Nine U.S. PICUs.
PATIENTS:Eighty-one children with sepsis-induced thrombocytopenia-associated multiple organ failure.
INTERVENTIONS:Therapeutic plasma exchange.
MEASUREMENTS AND MAIN RESULTS:Adjusted relative risk for 28-day mortality was modeled using standard multivariate regression with propensity score weighting to reduce covariate confounding. Change from baseline Pediatric Logistic Organ Dysfunction scores between therapeutic plasma exchange and no therapeutic plasma exchange differed in temporal pattern during the first week (p = 0.009). By day 4, mean Pediatric Logistic Organ Dysfunction score declined by 7.9 points (95% CI, –10.8 to –5.1) in the therapeutic plasma exchange–treated group compared with no change with no therapeutic plasma exchange. Use of therapeutic plasma exchange was associated with reduced 28-day mortality by multivariate analysis (adjusted relative risk, 0.45; 95% CI, 0.23–0.90; p = 0.02) and by propensity score weighting (adjusted relative risk, 0.46; 95% CI, 0.22–0.97; p = 0.04).
CONCLUSIONS:Therapeutic plasma exchange use in thrombocytopenia-associated multiple organ failure was associated with a decrease in organ dysfunction. After accounting for several risk factors, 28-day all-cause mortality was lower in children treated with therapeutic plasma exchange compared with those receiving no therapeutic plasma exchange. A multicenter randomized clinical trial is necessary to determine a causal relationship.
Since its introduction into the medical literature in the 1970s, the term multiple organ dysfunction syndrome (or some variant) has been applied broadly to any patient with >1 concurrent organ ...dysfunction. However, the epidemiology, mechanisms, time course, and outcomes among children with multiple organ dysfunction vary substantially. We posit that the term pediatric multiple organ dysfunction syndrome (or MODS) should be reserved for patients with a systemic pathologic state resulting from a common mechanism (or mechanisms) that affects numerous organ systems simultaneously. In contrast, children in whom organ injuries are attributable to distinct mechanisms should be considered to have additive organ system dysfunctions but not the syndrome of MODS. Although such differentiation may not always be possible with current scientific knowledge, we make the case for how attempts to differentiate multiple organ dysfunction from other states of additive organ dysfunctions can help to evolve clinical and research priorities in diagnosis, monitoring, and therapy from largely organ-specific to more holistic strategies.
Hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended ...that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH.
We conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival.
Twenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 μg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002).
Children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.
BACKGROUND:On the basis of laboratory cardiopulmonary resuscitation (CPR) investigations and limited adult data demonstrating that survival depends on attaining adequate arterial diastolic blood ...pressure (DBP) during CPR, the American Heart Association recommends using blood pressure to guide pediatric CPR. However, evidence-based blood pressure targets during pediatric CPR remain an important knowledge gap for CPR guidelines.
METHODS:All children ≥37 weeks’ gestation and <19 years old in Collaborative Pediatric Critical Care Research Network intensive care units with chest compressions for ≥1 minute and invasive arterial blood pressure monitoring before and during CPR between July 1, 2013, and June 31, 2016, were included. Mean DBP during CPR and Utstein-style standardized cardiac arrest data were collected. The hypothesis was that DBP ≥25 mm Hg during CPR in infants and ≥30 mm Hg in children ≥1 year old would be associated with survival. Primary outcome was survival to hospital discharge. Secondary outcome was survival to hospital discharge with favorable neurological outcome, defined as Pediatric Cerebral Performance Categories 1 to 3 or no worse than prearrest baseline. Multivariable Poisson regression models with robust error estimates were used to estimate the relative risk of outcomes.
RESULTS:Blinded investigators analyzed blood pressure waveforms during CPR from 164 children, including 60% <1 year old, 60% with congenital heart disease, and 54% after cardiac surgery. The immediate cause of arrest was hypotension in 67%, respiratory decompensation in 44%, and arrhythmia in 19%. Median duration of CPR was 8 minutes (quartiles, 3 and 27 minutes). Ninety percent survived the event, 68% with return of spontaneous circulation and 22% by extracorporeal life support. Forty-seven percent survived to hospital discharge, and 43% survived to discharge with favorable neurological outcome. Maintaining mean DBP ≥25 mm Hg in infants and ≥30 mm Hg in children ≥1 year old occurred in 101 of 164 children (62%) and was associated with survival (adjusted relative risk, 1.7; 95% confidence interval, 1.2–2.6; P=0.007) and survival with favorable neurological outcome (adjusted relative risk, 1.6; 95% confidence interval, 1.1–2.5; P=0.02).
CONCLUSIONS:These data demonstrate that mean DBP ≥25 mm Hg during CPR in infants and ≥30 mm Hg in children ≥1 year old was associated with greater likelihood of survival to hospital discharge and survival with favorable neurological outcome.
The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such ...as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient's clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.
Because pediatric trauma-related mortality continues to decline, metrics assessing morbidity are needed to evaluate the impact of treatment after injury. Based on its value for assessing children ...with traumatic brain injuries and other critical illnesses, Functional Status Scale (FSS), a tool that measures function in six domains (communication, feeding, mental, motor, sensory, and respiratory), was evaluated as an outcome measure for the overall population of injured children.
Children with at least one injury (Abbreviated Injury Scale AIS severity ≥1) surviving to discharge between December 2011 and April 2013 were identified in a previous study of intensive care unit admissions. Morbidity was defined as additional morbidity in any domain (domain FSS change ≥2 or 'new domain morbidity') and additional overall morbidity (total FSS change ≥3) between preinjury status and discharge. Associations between injury profiles and the development of morbidity were analyzed.
We identified 553 injured children, with a mean of 2.0 ± 1.9 injuries. New domain and overall morbidity were observed in 17.0% and 11.0% of patients, respectively. New domain morbidity was associated with an increasing number of body regions with an injury with AIS ≥ 2 (p < 0.001), with severe (AIS ≥ 4) head (p = 0.04) and spine (p = 0.01) injuries and with at moderately severe (AIS ≥ 2) lower extremity injuries (p = 0.01). New domain morbidity was more common among patients with severe spine and lower extremity injuries (55.6% and 48.7%, respectively), with greatest impact in the motor domain (55.6% and 43.6%, respectively). New domain morbidity was associated with increasing injury severity score, number of moderately severe injuries and number of body regions with more than a moderately severe injury (p < 0.001 for all).
Higher morbidity measured by the FSS is associated with increasing injury severity. These findings support the use of the FSS as a metric for assessing outcome after pediatric injury.
Prognostic/Epidemiologic, level III.
With continued attention to pediatric sepsis at both the clinical and policy levels, it is important to understand the quality of hospitals in terms of their pediatric sepsis mortality. We sought to ...develop a method to evaluate hospital pediatric sepsis performance using 30-day risk-adjusted mortality and to assess hospital variation in risk-adjusted sepsis mortality in a large state-wide sample.
Retrospective cohort study using administrative claims data.
Acute care hospitals in the state of Pennsylvania from 2011 to 2013.
Patients between the ages of 0-19 years admitted to a hospital with sepsis defined using validated International Classification of Diseases, Ninth revision, Clinical Modification, diagnosis and procedure codes.
None.
During the study period, there were 9,013 pediatric sepsis encounters in 153 hospitals. After excluding repeat visits and hospitals with annual patient volumes too small to reliably assess hospital performance, there were 6,468 unique encounters in 24 hospitals. The overall unadjusted mortality rate was 6.5% (range across all hospitals: 1.5-11.9%). The median number of pediatric sepsis cases per hospital was 67 (range across all hospitals: 30-1,858). A hierarchical logistic regression model for 30-day risk-adjusted mortality controlling for patient age, gender, emergency department admission, infection source, presence of organ dysfunction at admission, and presence of chronic complex conditions showed good discrimination (C-statistic = 0.80) and calibration (slope and intercept of calibration plot: 0.95 and -0.01, respectively). The hospital-specific risk-adjusted mortality rates calculated from this model varied minimally, ranging from 6.0% to 7.4%.
Although a risk-adjustment model for 30-day pediatric sepsis mortality had good performance characteristics, the use of risk-adjusted mortality rates as a hospital quality measure in pediatric sepsis is not useful due to the low volume of cases at most hospitals. Novel metrics to evaluate the quality of pediatric sepsis care are needed.
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