Creating a data dictionary for pediatric autonomic disorders.

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.

Assessment of comorbid symptoms in pediatric autonomic dysfunction.

PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.

Development of a Heart Rate Variability Risk Score to Predict Organ Dysfunction and Death in Critically Ill Children.

OBJECTIVES: Determine whether the Heart Rate Variability Dysfunction score, a novel age-normalized measure of autonomic nervous system dysregulation, is associated with the development of new or progressive multiple organ dysfunction syndrome or death in critically ill children. DESIGN, SETTING, AND PATIENTS: This was a retrospective, observational cohort study from 2012 to 2018. Patients admitted to the PICU with at least 12 hours of continuous heart rate data available from bedside monitors during the first 24 hours of admission were included in the analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Heart rate variability was measured using the integer heart rate variability, which is the sd of the heart rate sampled every 1 second over 5 consecutive minutes. The Heart Rate Variability Dysfunction score was derived from age-normalized values of integer heart rate variability and transformed, so that higher scores were indicative of lower integer heart rate variability and a proxy for worsening autonomic nervous system dysregulation. Heart Rate Variability Dysfunction score performance as a predictor of new or progressive multiple organ dysfunction syndrome and 28-day mortality were determined using the area under the receiver operating characteristic curve. Of the 7,223 patients who met inclusion criteria, 346 patients (4.8%) developed new or progressive multiple organ dysfunction syndrome, and 103 (1.4%) died by day 28. For every one-point increase in the median Heart Rate Variability Dysfunction score in the first 24 hours of admission, there was a 25% increase in the odds of new or progressive multiple organ dysfunction syndrome and a 51% increase in the odds of mortality. The median Heart Rate Variability Dysfunction score in the first 24 hours had an area under the receiver operating characteristic curve to discriminate new or progressive multiple organ dysfunction syndrome of 0.67 and to discriminate mortality of 0.80. These results were reproducible in a temporal validation cohort. CONCLUSIONS: The Heart Rate Variability Dysfunction score, an age-adjusted proxy for autonomic nervous system dysregulation derived from bedside monitor data is independently associated with new or progressive multiple organ dysfunction syndrome and mortality in PICU patients. The Heart Rate Variability Dysfunction score could potentially be used as a single continuous physiologic biomarker or as part of a multivariable prediction model to increase awareness of at-risk patients and augment clinical decision-making.

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

OBJECTIVES: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children. DESIGN: Nested case-control study. SETTING: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia. PATIENTS: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia. CONCLUSIONS: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.

Critical Illness and Cardiac Dysfunction in Anthracycline-Exposed Pediatric Oncology Patients.

OBJECTIVES: To determine if the presence of cardiac dysfunction in anthracycline-exposed pediatric oncology patients is associated with an increased frequency of PICU admission or mortality. DESIGN: Retrospective parallel cohort study. SETTING: PICU at an academic freestanding children's hospital. SUBJECTS: Children with oncologic diagnoses who received anthracyclines between January 2006 and December 2014 and were admitted to the hospital within 1 year of completion of therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Charts of 734 patients were reviewed and 545 were included in analysis. Anthracycline-exposed pediatric oncology patients with cardiac dysfunction were more likely to be admitted to the PICU than those without cardiac dysfunction (87% vs 37% rate of PICU admission). PICU admission was also associated with identified infection and higher cumulative anthracycline dose. Once admitted to the PICU, those anthracycline-exposed patients with cardiac dysfunction had significantly higher mortality (26% vs 6%) and longer length of stay (7 vs 2 d) than children without cardiac dysfunction. Patients with cardiac dysfunction were more likely to require mechanical ventilation (59% vs 18%), required more vasoactive medications for longer, and were more likely to develop fluid overload. Death within 1 year of ICU admission was associated with higher cumulative anthracycline dose. CONCLUSIONS: Children with cancer who received anthracyclines, especially at higher doses, and who develop cardiac dysfunction are at higher risk of critical illness, have higher rates of multiple organ dysfunction and higher rates of mortality than anthracycline-exposed patients without cardiac dysfunction.

Outcomes Associated With Multiple Organ Dysfunction Syndrome in Critically Ill Children With Hyperglycemia.

OBJECTIVES: Patterns and outcomes of multiple organ dysfunction syndrome are unknown in critically ill children with hyperglycemia. We aimed to determine whether tight glycemic control to a lower vs. higher range influenced timing, duration, or resolution of multiple organ dysfunction syndrome as well as characterize the clinical outcomes of subgroups of multiple organ dysfunction syndrome in children enrolled in the Heart And Lung Failure-Pediatric INsulin Titration trial. DESIGN: Planned secondary analysis of the multicenter Heart And Lung Failure-Pediatric INsulin Titration trial. SETTING: Thirty-five PICUs. PATIENTS: Critically ill children with hyperglycemia who received the Heart And Lung Failure-Pediatric INsulin Titration protocol from 2012 to 2016. INTERVENTIONS: Randomization to a lower versus higher glucose target group. MEASUREMENTS AND MAIN RESULTS: Of 698 patients analyzed, 48 (7%) never developed multiple organ dysfunction syndrome, 549 (79%) had multiple organ dysfunction syndrome without progression, 32 (5%) developed new multiple organ dysfunction syndrome, and 69 (10%) developed progressive multiple organ dysfunction syndrome. Of those whose multiple organ dysfunction syndrome resolved, 192 (34%) experienced recurrent multiple organ dysfunction syndrome. There were no significant differences in the proportion of multiple organ dysfunction syndrome subgroups between Heart And Lung Failure-Pediatric INsulin Titration glucose target groups. However, patients with new or progressive multiple organ dys function syndrome had fewer ICU-free days through day 28 than those without new or progressive multiple organ dysfunction syndrome, and progressive multiple organ dysfunction syndrome patients had fewer ICU-free days than those with new multiple organ dysfunction syndrome: median 25.1 days for never multiple organ dysfunction syndrome, 20.2 days for multiple organ dysfunction syndrome without progression, 18.6 days for new multiple organ dysfunction syndrome, and 0 days for progressive multiple organ dysfunction syndrome (all comparisons p < 0.001). Patients with recurrent multiple organ dysfunction syndrome experienced fewer ICU-free days than those without recurrence (median, 11.2 vs 22.8 d; p < 0.001). CONCLUSIONS: Tight glycemic control target range was not associated with differences in the proportion of new, progressive, or recurrent multiple organ dysfunction syndrome. New or progressive multiple organ dysfunction syndrome was associated with poor clinical outcomes, and progressive multiple organ dysfunction syndrome was associated with worse outcomes than new multiple organ dysfunction syndrome. In future studies, new multiple organ dysfunction syndrome and progressive multiple organ dysfunction syndrome may need to be considered separately, as they represent distinct subgroups with different, potentially modifiable risk factors. Patients with recurrent multiple organ dysfunction syndrome represent a newly characterized, high-risk group which warrants attention in future research.

Hyperglycemia at the Time of Acquiring Central Catheter-Associated Bloodstream Infections Is Associated With Mortality in Critically Ill Children.

OBJECTIVES: Hyperglycemia is common and may be a risk factor for nosocomial infections, including central catheter-associated bloodstream infections in critically ill children. It is unknown whether hyperglycemia at the time of acquiring central catheter-associated bloodstream infections in pediatric critical illness is associated with worse outcomes. We hypothesized that hyperglycemia (blood glucose concentration > 126 mg/dL [> 7 mmol/L]) at the time of acquiring central catheter-associated bloodstream infections (from 4 d prior to the day of first positive blood culture, i.e., central catheter-associated bloodstream infections) in critically ill children is common and associated with ICU mortality. DESIGN: Retrospective observational cohort study. SETTING: Fifty-five-bed PICU and 26-bed cardiac ICU at an academic freestanding children's hospital. PATIENTS: One hundred sixteen consecutively admitted critically ill children from January 1, 2008, to June 30, 2012, who were 0-21 years with central catheter-associated bloodstream infections were included. We excluded children with diabetes mellitus, metabolic disorders, and those with a "do not attempt resuscitation" order. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study cohort had an overall ICU mortality of 23%, with 48% of subjects developing hyperglycemia at the time of acquiring central catheter-associated bloodstream infections. Compared with survivors, nonsurvivors experienced more hyperglycemia both at the time of acquiring central catheter-associated bloodstream infections and subsequently. Median blood glucose at the time of acquiring central catheter-associated bloodstream infections was higher in nonsurvivors compared with survivors (139.5 mg/dL [7.7 mmol/L] vs 111 mg/dL [6.2 mmol/L]; p < 0.001) with 70% of nonsurvivors experiencing blood glucose greater than 126 mg/dL (> 7 mmol/L) during the 7 days following central catheter-associated bloodstream infections (in comparison to 45% of survivors; p = 0.03). After controlling for severity of illness and interventions, hyperglycemia at the time of acquiring central catheter-associated bloodstream infections was independently associated with ICU mortality (adjusted odds ratio, 1.9; 95% CI, 1.1-6.4; p = 0.03), in addition to other risk factors for ICU mortality (vasopressor use and severity of organ dysfunction). CONCLUSIONS: Hyperglycemia at the time of acquiring central catheter-associated bloodstream infections is common and associated with ICU mortality in critically ill children. Strategies to monitor and control blood glucose to avoid hyperglycemia may improve outcomes in critically ill children experiencing central catheter-associated bloodstream infections.

A comprehensive wireless neurological and cardiopulmonary monitoring platform for pediatrics.

Neurodevelopment in the first 10 years of life is a critical time window during which milestones that define an individual's functional potential are achieved. Comprehensive multimodal neurodevelopmental monitoring is particularly crucial for socioeconomically disadvantaged, marginalized, historically underserved and underrepresented communities as well as medically underserved areas. Solutions designed for use outside the traditional clinical environment represent an opportunity for addressing such health inequalities. In this work, we present an experimental platform, ANNE EEG, which adds 16-channel cerebral activity monitoring to the existing, USA FDA-cleared ANNE wireless monitoring platform which provides continuous electrocardiography, respiratory rate, pulse oximetry, motion, and temperature measurements. The system features low-cost consumables, real-time control and streaming with widely available mobile devices, and fully wearable operation to allow a child to remain in their naturalistic environment. This multi-center pilot study successfully collected ANNE EEG recordings from 91 neonatal and pediatric patients at academic quaternary pediatric care centers and in LMIC settings. We demonstrate the practicality and feasibility to conduct electroencephalography studies with high levels of accuracy, validated via both quantitative and qualitative metrics, compared against gold standard systems. An overwhelming majority of parents surveyed during studies indicated not only an overall preference for the wireless system, but also that its use would improve their children's physical and emotional health. Our findings demonstrate the potential for the ANNE system to perform multimodal monitoring to screen for a variety of neurologic diseases that have the potential to negatively impact neurodevelopment.

Informed consent for bedside procedures in the pediatric intensive care unit: a preliminary report.

OBJECTIVES: No uniform guidelines exist regarding informed consent for bedside procedures in the intensive care unit (ICU), and practice varies widely between institutions. Neither guidelines nor data exist to help pediatric ICU (PICU) directors craft procedural consent policies. We conducted an exploratory study to explore the impact on patients, parents, and healthcare providers of a requirement for informed consent for bedside procedures in the PICU and to describe parental and provider beliefs regarding procedural consent. DESIGN: Prospective, observational and survey-based exploratory study. SETTING: Single-center, tertiary care, university-affiliated PICU. PATIENTS: Children admitted to the PICU and undergoing an invasive bedside procedure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During two 14-day periods, all bedside procedures conducted in the PICU were identified. Consent forms were reviewed, and parents and the healthcare providers who participated in the consent discussion were invited to complete a brief verbal questionnaire regarding the consent process. Quantitative data are presented using descriptive statistics and qualitative data were analyzed using thematic coding. During the study period, 50 bedside procedures were performed. Informed consent was not obtained for two emergent procedures. Only the first procedure on a child was included in the study, leaving 41 informed consent discussions for analysis. Consent was obtained in person in 33 cases (80%) and over the phone for the remainder. The median reported duration of the informed consent discussion was 5 mins. Ninety-six percent of parents correctly recalled what procedure had been performed, and 92% correctly recalled at least one reason for the procedure, but only 58% recalled at least one risk of the procedure. Parents viewed themselves as the primary decision makers, and many parents believed that their refusal of consent would be honored even if it would potentially harm the child. However, no parent refused or even significantly resisted giving consent for a procedure recommended by their child's healthcare provider. CONCLUSION: Parental consent for invasive bedside procedures in the PICU can be obtained reliably and without posing an undue time burden on healthcare providers. Most parents perceive a real decision making opportunity surrounding invasive procedures, but agree readily to the recommendations of their healthcare providers.

Wireless, Skin-Interfaced Devices for Pediatric Critical Care: Application to Continuous, Noninvasive Blood Pressure Monitoring.

Indwelling arterial lines, the clinical gold standard for continuous blood pressure (BP) monitoring in the pediatric intensive care unit (PICU), have significant drawbacks due to their invasive nature, ischemic risk, and impediment to natural body movement. A noninvasive, wireless, and accurate alternative would greatly improve the quality of patient care. Recently introduced classes of wireless, skin-interfaced devices offer capabilities in continuous, precise monitoring of physiologic waveforms and vital signs in pediatric and neonatal patients, but have not yet been employed for continuous tracking of systolic and diastolic BP-critical for guiding clinical decision-making in the PICU. The results presented here focus on materials and mechanics that optimize the system-level properties of these devices to enhance their reliable use in this context, achieving full compatibility with the range of body sizes, skin types, and sterilization schemes typically encountered in the PICU. Systematic analysis of the data from these devices on 23 pediatric patients, yields derived, noninvasive BP values that can be quantitatively validated against direct recordings from arterial lines. The results from this diverse cohort, including those under pharmacological protocols, suggest that wireless, skin-interfaced devices can, in certain circumstances of practical utility, accurately and continuously monitor BP in the PICU patient population.

Heart rate variability as a marker of recovery from critical illness in children.

OBJECTIVES: The purpose of this study was to Identify whether changes in heart rate variability (HRV) could be detected as critical illness resolves by comparing HRV from the time of pediatric intensive care unit (PICU) admission with HRV immediately prior to discharge. We also sought to demonstrate that HRV derived from electrocardiogram (ECG) data from bedside monitors can be calculated in critically-ill children using a real-time, streaming analytics platform. METHODS: This was a retrospective, observational pilot study of 17 children aged 0 to 18 years admitted to the PICU of a free-standing, academic children's hospital. Three time-domain measures of HRV were calculated in real-time from bedside monitor ECG data and stored for analysis. Measures included: root mean square of successive differences between NN intervals (RMSSD), percent of successive NN interval differences above 50 ms (pNN50), and the standard deviation of NN intervals (SDNN). RESULTS: HRV values calculated from the first and last 24 hours of PICU stay were analyzed. Mixed effects models demonstrated that all three measures of HRV were significantly lower during the first 24 hours compared to the last 24 hours of PICU admission (p<0.001 for all three measures). In models exploring the relationship between time from admission and log HRV values, the predicted average HRV remained consistently higher in the last 24 hours of PICU stay compared to the first 24 hours. CONCLUSION: HRV was significantly lower in the first 24 hours compared to the 24 hours preceding PICU discharge, after resolution of critical illness. This demonstrates that it is feasible to detect changes in HRV using an automated, streaming analytics platform. Continuous tracking of HRV may serve as a marker of recovery in critically ill children.

Autonomic Nervous System Dysfunction in Pediatric Sepsis.

The autonomic nervous system (ANS) plays a major role in maintaining homeostasis through key adaptive responses to stress, including severe infections and sepsis. The ANS-mediated processes most relevant during sepsis include regulation of cardiac output and vascular tone, control of breathing and airway resistance, inflammation and immune modulation, gastrointestinal motility and digestion, and regulation of body temperature. ANS dysfunction (ANSD) represents an imbalanced or maladaptive response to injury and is prevalent in pediatric sepsis. Most of the evidence on ANSD comes from studies of heart rate variability, which is a marker of ANS function and is inversely correlated with organ dysfunction and mortality. In addition, there is evidence that other measures of ANSD, such as respiratory rate variability, skin thermoregulation, and baroreflex and chemoreflex sensitivity, are associated with outcomes in critical illness. The relevance of understanding ANSD in the context of pediatric sepsis stems from the fact that it might play an important role in the pathophysiology of sepsis, is associated with outcomes, and can be measured continuously and noninvasively. Here we review the physiology and dysfunction of the ANS during critical illness, discuss methods for measuring ANS function in the intensive care unit, and review the diagnostic, prognostic, and therapeutic value of understanding ANSD in pediatric sepsis.

Antibodies that inhibit binding of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A and to the C terminus of merozoite surface protein 1 correlate with reduced placental malaria in Cameroonian women.

Plasmodium falciparum-infected erythrocytes often sequester in the placenta of pregnant women, producing placental malaria, a condition that can compromise the health of the developing fetus. Scientists are hopeful that a vaccine can be developed to prevent this condition. Immunological mechanisms responsible for eliminating parasites from the placenta remain unclear, but antibodies to the carboxyl-terminal 19-kDa segment of the merozoite surface protein 1 (MSP1-19), the ring-infected erythrocyte surface antigen (RESA), and an erythrocyte-surface ligand that binds chondroitin sulfate A (CSA-L) have been implicated. In addition, antibodies to sporozoite and liver-stage antigens could reduce initial parasite burdens. This study sought to determine if antibodies to the circumsporozoite protein (CSP), liver-stage antigen 1 (LSA1), RESA, MSP1-19, or CSA-L correlated with either the absence of placental parasites or low placental parasitemias. Using a frequency-matched case-control study design, we compared antibody levels in women (gravidity 1 to 11) with and without placental malaria. Results showed that women who were antibody negative for MSP1-19 were at a higher risk of having placental malaria than women with antibodies (P < 0.007). Furthermore, an association between high levels of antibodies that blocked the binding of infected erythrocytes to CSA and low placental parasitemias was observed (P = 0.02). On the other hand, women with high antibody levels at term to CSP, LSA1, and RESA were more likely to have placental malaria than antibody-negative women. Since antibodies to MSP1-19 and CSA-L were associated with reduced placental malaria, both antigens show promise for inclusion in a vaccine for women of child-bearing age.