Decreasing ICU and Hospital Length of Stay through a Standardized Respiratory Therapist-driven Electronic Clinical Care Pathway for Status Asthmaticus.

Introduction: Status asthmaticus (SA) is a cause of many pediatric hospitalizations. This study sought to evaluate how a standardized asthma care pathway (ACP) in the electronic medical record impacted the length of stay (LOS). Methods: An interdisciplinary team internally validated a standardized respiratory score for patients admitted with SA to a 25-bed pediatric intensive care unit (PICU) at a tertiary children's hospital. The respiratory score determined weaning schedules for albuterol and steroid therapies. In addition, pharmacy and information technology staff developed an electronic ACP within our electronic medical record system using best practice alerts. These best practice alerts informed staff to initiate the pathway, wean/escalate treatment, transition to oral steroids, transfer level of care, and complete discharge education. The PICU, stepdown ICU (SD ICU), and acute care units implemented the clinical pathway. Pre- and postintervention metrics were assessed using process control charts and compared using Welch's t tests with a significance level of 0.05. Results: Nine hundred two consecutive patients were analyzed (598 preintervention, 304 postintervention). Order set utilization significantly increased from 68% to 97% (P < 0.001), PICU LOS decreased from 38.4 to 31.1 hours (P = 0.013), and stepdown ICU LOS decreased from 25.7 to 20.9 hours (P = 0.01). Hospital LOS decreased from 59.5 to 50.7 hours (P = 0.003), with cost savings of $1,215,088 for the patient cohort. Conclusions: Implementing a standardized respiratory therapist-driven ACP for children with SA led to significantly increased order set utilization and decreased ICU and hospital LOS. Leveraging information technology and standardized pathways may improve care quality, outcomes, and costs for other common diagnoses.

The use of vitamin K for coagulopathy in critically ill children.

OBJECTIVES: Coagulopathy is associated with increased mortality in children in the intensive care unit (ICU). Recommended management of vitamin K-deficient coagulopathy is vitamin K administration. The goal of this study was to evaluate vitamin K administration for coagulopathy in critically ill children and determine a relationship between vitamin K dose and change in prothrombin time (PT) and international normalized ratio (INR). METHODS: This retrospective cohort study reviewed electronic medical records of patients ≤17 years who received vitamin K for acute coagulopathy in the pediatric ICU from January 2013 to January 2021. Patients receiving vitamin K antagonists were excluded. Effectiveness data included change in PT/INR after vitamin K administration. Safety data included incidence of hypersensitivity or anaphylaxis. RESULTS: A total of 310 patients (median age 6.8 years, range 22 days-17.7 years) received vitamin K. A median of three doses (range 1-8) and 0.14 mg/kg per dose (range 0.09-0.22 mg/kg) were given, most frequently intravenously (892/949, 94%). Most patients (304/310, 98%) had at least one risk factor for vitamin K deficiency. Mean PT/INR was 21.5/2.1 prior to vitamin K administration, which decreased by 4.4 (SD = 9.0, 95% CI 16.011 to 18.015, p < 0.001) and 0.5 (SD = 1.0, 95% CI 1.490 to 1.705, p < 0.001) to means of 17.0 and 1.6, respectively, after the first vitamin K dose. No linear relationship was found between vitamin K dose and change in PT/INR. No hypersensitivity or anaphylaxis occurred following vitamin K administration; 27% (84/310) of patients died. CONCLUSIONS: Administration of vitamin K is effective and safe for the management of vitamin K-deficient coagulopathy in critically ill pediatric patients. Further study is needed to determine a relationship between vitamin K dose and change in PT/INR.

Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program.

OBJECTIVE: Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. METHODS: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. RESULTS: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range = 0-74.5), and patients were taking a median of three (range = 0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%). SIGNIFICANCE: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

Acute COVID-19 Infection in a Pediatric Patient with ROHHAD.

The novel coronavirus (severe acute respiratory syndrome coronavirus-2) has led to a global pandemic. In the adult population, coronavirus disease 2019 (COVID-19) has been found to cause multiorgan system damage with predicted long-term sequelae. We present a case of a 10-year-old boy with a history of ROHHAD (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation) who presented with hypoxia, emesis, and abdominal pain. Imaging found bilateral ground glass opacities in the lungs and a pericardial effusion. Laboratory evaluation was concerning for elevated inflammatory markers. Remdesivir, hydroxychloroquine, and anticoagulation (heparin and enoxaparin) were utilized. The patient's severe respiratory failure was managed with conventional mechanical ventilation, inhaled nitric oxide, and airway pressure release ventilation. We hope that this report provides insight into the course and management of the severe acute pediatric COVID-19 patient, specifically with underlying comorbidities such as ROHHAD. Clinical trial registration is none.

Endotracheal Tube Placement Confirmation with Bedside Ultrasonography in the Pediatric Intensive Care Unit: A Validation Study.

Critically ill patients who are intubated undergo multiple chest X-rays (CXRs) to determine endotracheal tube position; however, other modalities can save time, medical expenses, and radiation exposure. In this article, we evaluated the validity and interrater reliability of ultrasound to confirm endotracheal tube (ETT) position in patients. A prospective study was performed on intubated patients with cuffed ETTs. The accuracy of ultrasound to confirm correct ETT placement in 92 patients was 97.8%. Sensitivity, positive predictive value, and agreement of 97.7, 93.3, and 91.3% were found on comparing ultrasound to CXR findings. Ultrasound is feasible, reliable, and has good interrater reliability in assessing correct ETT position in children.

The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.

Better Etiquette for Effective Paging (B.E.E.P.)-Improving Daily In-hospital Communications in the Pediatric ICU.

INTRODUCTION: Paging is a vital part of patient care that allows quick contact between physicians and other hospital personnel. There was no structured way to send a page to physicians at our institution. We hypothesized that by standardizing paging format, scheduling laboratory draw times, and using order clean-up sheets, through a bundle of interventions called Better Etiquette for Effective Paging, we would decrease the number of pages received on the pediatric intensive care unit (PICU) resident pager by 15%. METHODS: This project was a quality improvement initiative in a 25-bed multidisciplinary PICU in a tertiary children's hospital. Baseline data collection was performed in December 2015, categorized by time of day received and type of page. Interventions were paging standards to include relevant information, scheduling laboratory draw times, and order clean-up sheets. We collected postintervention data over 3 years to monitor for sustained change. RESULTS: The average number of pages decreased from a baseline of 4.71 pages/patient/d in 2015 to 3.70 in 2016 (21% decrease), 3.32 in 2017 (30% decrease), and 2.74 in 2018 (42% decrease). The average PRISM 3 score remained similar in all sets (2.52, 2.50, 2.10, and 2.35). The standardized mortality ratio was not adversely affected by the decrease in pages (0.58, 1.07, 1.19, and 0). CONCLUSION: Standardizing the format of pages and using scheduled laboratory times with order clean-up sheets has decreased the number of pages/patient/d in the PICU by 42% without adversely affecting patient care. We can continue to improve communication among the patient care team by emphasizing efficient, standardized communication using Better Etiquette for Effective Paging.

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.

HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vß chains results in Vß skewing, whereby T cells with specific Vß chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRß variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vß chain encoded by TRBV11-2 (Vß21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.

Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.

Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome.

Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares many clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. The superantigen specificity for binding different Vß-chains results in Vß-skewing, whereby T cells with specific Vß-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Βeta Variable gene (TRBV)11-2. Furthermore, TRBV11-2 skewing was remarkably correlated with MIS-C severity and serum cytokine levels. Further analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanding TRBV11-2 clones revealed extensive junctional diversity, indicating a superantigen-mediated selection process for TRBV expansion. In silico modelling indicates that polyacidic residues in TCR Vß11-2 engage in strong interactions with the superantigen-like motif of SARS-CoV-2 spike glycoprotein. Overall, our data indicate that the immune response in MIS-C is consistent with superantigenic activation.

Impacting Satisfaction, Learning, and Efficiency Through Structured Interdisciplinary Rounding in a Pediatric Intensive Care Unit: A Quality Improvement Project.

BACKGROUND: Daily rounds in many pediatric intensive care units (PICUs) vary in quality, duration, and participation. We hypothesized that implementing structured interdisciplinary bedside rounds (SIBR®) would improve our rounding process. METHODS: This was a quality improvement initiative in a 25-bed multidisciplinary PICU in a tertiary children's hospital. Baseline data included rounding duration; participation of nurses, respiratory care practitioners (RCP), parents; and physician order read-back practices. Interventions were implementing pre-rounding huddles, changing the start of the rounding week, and instituting a SIBR model. All staff, consecutive patients and parents participated over 18 months. We used Mann-Whitney, z-test, and t-tests for statistical analysis with a significance level of 0.05. We tracked data with a statistical process control chart. RESULTS: Rounds participation increased for nurses (88% to 100%), RCPs (13% to 61%), and families (24% to 49%) (all p <0.001). Physician order read-back increased (41% to 79%) (p<0.001). The median length of stay (LOS) decreased from 2.1 to 1.9 days (p=0.004) with no changes in mortality or readmissions. The proportion of top responses from family surveys increased from 0.69 to 0.76 (p<0.001). PICU rounding duration (minutes/patient) decreased from 17.1 to 11.3. Most resident physicians felt SIBR positively impacted their education (70%), was more effective than rounds without structure (97%), and that family presence positively impacted learning (70%). CONCLUSIONS: Implementing a SIBR process in our PICU resulted in greater family and staff satisfaction, improved workflow and decreased rounding time by 34% without compromising education. LOS decreased significantly with no increases in mortality or readmissions.

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

An Observational Study of Severe Pertussis in 100 Infants ≤120 Days of Age.

BACKGROUND: Pertussis in young infants is a unique, severe, afebrile, cough illness that is frequently fatal. METHODS: All pertussis cases ≤120 days of age admitted to a pediatric intensive care unit in California between October 1, 2013, and April 25, 2015, were evaluated. RESULTS: Of 100 pertussis patients ≤120 days of age admitted to pediatric intensive care unit, there were 5 deaths. The white blood cell counts in the fatal cases were significantly higher than in the nonfatal cases. Thirty-four percent of patients were intubated, 18% received inotropic and/or vasoactive support, 22% received steroid, 4% received extracorporal membrane oxygenation, and 3% underwent exchange blood transfusion. The median age at the time of illness onset in the patients who died was 23 days. CONCLUSIONS: These data, as well as data from previous California studies, suggest updated strategies for the management of severe pertussis. These include perform serial white blood cell counts, treat all presumptive cases with azithromycin, evaluate for pulmonary hypertension, intubate and administer oxygen for apneic episodes and administer inotropic/vasoactive agents for cardiogenic shock. Do not administer steroids or nitric oxide. Criteria for exchange blood transfusion therapy for leukocytosis with lymphocytosis are suggested.

Oral, jaw, and neck injury in infants and children: from abusive trauma or intubation?

OBJECTIVES: The objective of this study was to identify the incidence of oral, jaw, and neck injury secondary to endotracheal intubation in young children. METHODS: This prospective observational study was conducted in the pediatric intensive care unit at a level 1 trauma center. From October 1998 to January 1999 and November 2007 to April 2008, all intubated patients younger than 3 years with no prior oral procedures were examined within 24 hours of intubation. A standardized form was used to record injuries. Separately, medical records were reviewed for prior injuries. Chi-square/Fisher exact test was used for statistical analysis. RESULTS: Of 105 patients included in the study, 12 had oral, jaw, or neck injury. One patient had a hard palate injury from a pen cap in his mouth during a seizure. Another broke a tooth biting the laryngoscope blade (the only injury directly attributable to intubation). The remaining 10 patients were determined to be those who experienced abusive trauma. The overall incidence of injury directly from intubation was 0.9%. Oral, jaw, and neck injuries were all significantly associated with abusive trauma (P < 0.001). Eleven patients had difficult intubations: 9 had no injuries, 1 experienced abusive trauma and the second was the patient who broke his tooth during intubation. CONCLUSIONS: Oral, jaw, or neck injury in young children is rarely caused by endotracheal intubation, regardless of difficulty during the procedure.