Ron Reeder

A FUNCTIONAL VERSION OF THE ARCH MODEL

Improvements in data acquisition and processing techniques have led to an almost continuous flow of information for financial data. High-resolution tick data are available and can be quite conveniently described by a continuous-time process. It is therefore natural to ask for possible extensions of financial time series models to a functional setup. In this paper we propose a functional version of the popular autoregressive conditional heteroskedasticity model. We will establish conditions for the existence of a strictly stationary solution, derive weak dependence and moment conditions, show consistency of the estimators, and perform a small empirical study demonstrating how our model matches with real data.

Delirium in Critically Ill Children: An International Point Prevalence Study*

Objectives: To determine prevalence of delirium in critically ill children and explore associated risk factors. Design: Multi-institutional point prevalence study. Setting: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. Patients: All children admitted to the pediatric critical care units on designated study days (n = 994). Intervention: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. Measurements and Main Results: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. Conclusions: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.

Factors Associated with Bleeding and Thrombosis in Children Receiving Extracorporeal Membrane Oxygenation

Rationale: Extracorporeal membrane oxygenation (ECMO) is used for respiratory and cardiac failure in children but is complicated by bleeding and thrombosis. Objectives: (1) To measure the incidence of bleeding (blood loss requiring transfusion or intracranial hemorrhage) and thrombosis during ECMO support; (2) to identify factors associated with these complications; and (3) to determine the impact of these complications on patient outcome. Methods: This was a prospective, observational cohort study in pediatric, cardiac, and neonatal intensive care units in eight hospitals, carried out from December 2012 to September 2014. Measurements and Main Results: ECMO was used on 514 consecutive patients under age 19 years. Demographics, anticoagulation practices, severity of illness, circuitry components, bleeding, thrombotic events, and outcome were recorded. Survival was 54.9%. Bleeding occurred in 70.2%, including intracranial hemorrhage in 16%, and was independently associated with higher daily risk of mortality. Circuit component changes were required in 31.1%, and patient‐related clots occurred in 12.8%. Laboratory sampling contributed to transfusion requirement in 56.6%, and was the sole reason for at least one transfusion in 42.2% of patients. Pump type was not associated with bleeding, thrombosis, hemolysis, or mortality. Hemolysis was predictive of subsequent thrombotic events. Neither hemolysis nor thrombotic events increased the risk of mortality. Conclusions: The incidences of bleeding and thrombosis are high during ECMO support. Laboratory sampling is a major contributor to transfusion during ECMO. Strategies to reduce the daily risk of bleeding and thrombosis, and different thresholds for transfusion, may be appropriate subjects of future trials to improve outcomes of children requiring this supportive therapy.

Treatment of Pediatric Septic Shock With the Surviving Sepsis Campaign Guidelines and Picu Patient Outcomes

Objectives: The Surviving Sepsis Campaign recommends rapid recognition and treatment of severe sepsis and septic shock. Few reports have evaluated the impact of these recommendations in pediatrics. We sought to determine if outcomes in patients who received initial care compliant with the Surviving Sepsis Campaign time goals differed from those treated more slowly. Design: Single center retrospective cohort study. Setting: Emergency department and PICU at an academic children’s hospital. Patients: Three hundred twenty-one patients treated for septic shock in the emergency department and admitted directly to the PICU. Interventions: None. Measurements and Main Results: The exposure was receipt of emergency department care compliant with the Surviving Sepsis Campaign recommendations (delivery of IV fluids, IV antibiotics, and vasoactive infusions within 1 hr of shock recognition). The primary outcome was development of new or progressive multiple organ dysfunction syndrome. Secondary outcomes included mortality, need for mechanical ventilation or vasoactive medications, and hospital and PICU length of stay. Of the 321 children studied, 117 received Surviving Sepsis Campaign compliant care in the emergency department and 204 did not. New or progressive multiple organ dysfunction syndrome developed in nine of the patients (7.7%) who received Surviving Sepsis Campaign compliant care and 25 (12.3%) who did not (p = 0.26). There were 17 deaths; overall mortality rate was 5%. There were no significant differences between groups in any of the secondary outcomes. Although only 36% of patients met the Surviving Sepsis Campaign guideline recommendation of bundled care within 1 hour of shock recognition, 75% of patients received the recommended interventions in less than 3 hours. Conclusions: Treatment for pediatric septic shock in compliance with the Surviving Sepsis Campaign recommendations was not associated with better outcomes compared with children whose initial therapies in the emergency department were administered more slowly. However, all patients were treated rapidly and we report low morbidity and mortality. This underscores the importance of rapid recognition and treatment of septic shock.

Detecting changes in functional linear models

We observe two sequences of curves which are connected via an integral operator. Our model includes linear models as well as autoregressive models in Hilbert spaces. We wish to test the null hypothesis that the operator did not change during the observation period. Our method is based on projecting the observations onto a suitably chosen finite dimensional space. The testing procedure is based on functionals of the weighted residuals of the projections. Since the quadratic form is based on estimating the long-term covariance matrix of the residuals, we also provide some results on Bartlett-type estimators.

Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome.

Objectives: We hypothesize that three inflammation pathobiology phenotypes are associated with increased inflammation, proclivity to develop features of macrophage activation syndrome, and multiple organ failure-related death in pediatric severe sepsis. Design: Prospective cohort study comparing children with severe sepsis and any of three phenotypes: 1) immunoparalysis-associated multiple organ failure (whole blood ex vivo tumor necrosis factor response to endotoxin < 200 pg/mL), 2) thrombocytopenia-associated multiple organ failure (new onset thrombocytopenia with acute kidney injury and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity < 57%), and/or 3) sequential multiple organ failure with hepatobiliary dysfunction (respiratory distress followed by liver dysfunction with soluble Fas ligand > 200 pg/mL), to those without any of these phenotypes. Setting: Tertiary children’s hospital PICU. Patients: One hundred consecutive severe sepsis admissions. Interventions: Clinical data were recorded daily, and blood was collected twice weekly. Measurements and Main Results: Multiple organ failure developed in 75 cases and eight died. Multiple organ failure cases with any of the three inflammation phenotypes (n = 37) had higher inflammation (C-reactive protein, p = 0.009 and ferritin, p < 0.001) than multiple organ failure cases without any of these phenotypes (n = 38) or cases with only single organ failure (n = 25). Development of features of macrophage activation syndrome and death were more common among multiple organ failure cases with any of the phenotypes (macrophage activation syndrome: 10/37, 27%; death: 8/37, 22%) compared to multiple organ failure cases without any phenotype (macrophage activation syndrome: 1/38, 3%; p = 0.003 and death: 0/38, 0%; p = 0.002). Conclusions: Our approach to phenotype categorization remains hypothetical, and the phenotypes identified need to be confirmed in multicenter studies of pediatric multiple organ dysfunction syndrome.

High Reliability Pediatric Septic Shock Quality Improvement Initiative and Decreasing Mortality

BACKGROUND AND OBJECTIVE: Septic shock impacts mortality, morbidity, and health care costs. A quality improvement (QI) initiative was launched to improve early recognition and timely treatment of patients with septic shock in a pediatric emergency department (PED). Our primary aim was to describe the longitudinal effectiveness of the program, iterative changes in clinical practice, and associated outcomes. METHODS: We implemented multiple interventions during our QI initiative (February 2007 to December 2014). Analysis of compliance and outcomes focused on a bundle consisting of: (1) timely antibiotics, (2) intravenous fluids (IVF) for rapid reversal of perfusion abnormalities and/or hypotension. Logistic regression was used to obtain adjusted odds ratios (ORs) for death and pediatric ICU (PICU) admission. RESULTS: A total of 1380 patients were treated for septic shock; 93% met screening criteria at triage. Implementation of the various processes improved timely interventions. One example included implementation of a sepsis order set, after which the mean proportion of patients receiving timely antibiotics increased to its highest rate. The odds of death were 5 times as high for children who did not receive bundle-compliant care (OR, 5.0 [95% Confidence Interval 1.9, 14.3]) compared with those who did (OR, 0.20 [95% Confidence Interval 0.07, 0.53]). Among PICU admitted patients, the odds of mortality were greater for children who presented with abnormal mental status and a higher pediatric index of mortality 2 score. CONCLUSIONS: QI methodology improved septic shock program goal adherence and decreased mortality without increasing PICU admissions or PED length of stay over the 8-year period, supporting continued emphasis on early recognition, timely IVF resuscitation, and antibiotic administration.

Morbidity and mortality prediction in pediatric heart surgery: Physiological profiles and surgical complexity

Objectives Outcome prediction for pediatric heart surgery has focused on mortality but mortality has been significantly reduced over the past 2 decades. Clinical care practices now emphasize reducing morbidity. Physiology‐based profiles assessed by the Pediatric Risk of Mortality (PRISM) score are associated with new significant functional morbidity detected at hospital discharge. Our aims were to assess the relationship between new functional morbidity and surgical risk categories (Risk Adjustment for Congenital Heart Surgery [RACHS] and Society for Thoracic Surgery Congenital Heart Surgery Database Mortality Risk [STAT]), measure the performance of 3‐level (intact survival, survival with new functional morbidity, or death) and 2‐level (survival or death) PRISM prediction algorithms, and assess whether including RACHS or STAT complexity categories improves the PRISM predictive performance. Methods Patients (newborn to age 18 years) were randomly selected from 7 sites (December 2011‐April 2013). Morbidity (using the Functional Status Scale) and mortality were assessed at hospital discharge. The most recently published PRISM algorithms were tested for goodness of fit, and discrimination with and without the RACHS and STAT complexity categories. Results The mortality rate in the 1550 patients was 3.2%. Significant new functional morbidity rate occurred in 4.8%, increasing from 1.8% to 13.9%, 1.7%, and 12.9% from the lowest to the highest RACHS and STAT categories, respectively. The 3‐level and 2‐level PRISM models had satisfactory goodness of fit and substantial discriminative ability. Inclusion of RACHS and STAT complexity categories did not improve model performance. Conclusions Both mortality and new, functional morbidity are important outcomes associated with surgical complexity and can be predicted using PRISM algorithms. Adding surgical complexity to the physiologic profiles does not improve predictor performance.

Functional Status of Neonatal and Pediatric Patients After Extracorporeal Membrane Oxygenation

Objectives: To describe functional status at hospital discharge for neonatal and pediatric patients treated with extracorporeal membrane oxygenation, and identify factors associated with functional status and mortality. Design: Secondary analysis of observational data collected by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014. Setting: Eight hospitals affiliated with the Collaborative Pediatric Critical Care Research Network. Patients: Patients were less than 19 years old and treated with extracorporeal membrane oxygenation. Interventions: Functional status was evaluated among survivors using the Functional Status Scale. Total Functional Status Scale scores range from 6 to 30 and are categorized as 6–7 (good), 8–9 (mildly abnormal), 10–15 (moderately abnormal), 16–21 (severely abnormal), and greater than 21 (very severely abnormal). Measurements and Main Results: Of 514 patients, 267 (52%) were neonates (⩽ 30 d old). Indication for extracorporeal membrane oxygenation was respiratory for 237 (46%), cardiac for 207 (40%), and extracorporeal cardiopulmonary resuscitation for 70 (14%). Among 282 survivors, 89 (32%) had good, 112 (40%) mildly abnormal, 67 (24%) moderately abnormal, and 14 (5%) severely or very severely abnormal function at hospital discharge. Among neonates, development of renal failure and longer hospitalization were independently associated with worse Functional Status Scale. Chronic conditions, prematurity, venoarterial extracorporeal membrane oxygenation, increased red cell transfusion in the first 24 hours of extracorporeal membrane oxygenation, and longer extracorporeal membrane oxygenation duration were independently associated with mortality. Among pediatric patients, chronic neurologic conditions, tracheostomy or home ventilator, extracorporeal cardiopulmonary resuscitation, hepatic dysfunction, and longer ICU stay were independently associated with worse Functional Status Scale. Chronic cardiac conditions, hepatic dysfunction, and neurologic or thrombotic complications were independently associated with mortality. Achieving blood lactate concentration less than or equal to 2 mmol/L during extracorporeal membrane oxygenation was independently associated with survival in both neonatal and pediatric patients. Conclusions: In this study, about half of extracorporeal membrane oxygenation patients survived with good, mildly abnormal, or moderately abnormal function at hospital discharge. Patient and extracorporeal membrane oxygenation-related factors are associated with functional status and mortality.

Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival

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.