Prehospital Recognition and Management of Pediatric Sepsis: A Qualitative Assessment.

BACKGROUND AND PURPOSE: Sepsis is a life-threatening disease in children and is a leading cause of morbidity and mortality. Early prehospital recognition and management of children with sepsis may have significant effects on the timely resuscitation of this high-risk clinical condition. However, the care of acutely ill and injured children in the prehospital setting can be challenging. This study aims to understand barriers, facilitators, and attitudes regarding recognition and management of pediatric sepsis in the prehospital setting. METHODS: This was a qualitative study of EMS professionals participating in focus groups using a grounded theory-based design to gather information on recognition and management of septic children in the prehospital setting. Focus groups were held for EMS administrators and medical directors. Separate focus groups were held for field clinicians. Focus groups were conducted via video conference until saturation of ideas was reached. Using consensus methodology, transcripts were coded in an iterative process. Data were then organized into positive and negative factors based on the validated PRECEDE-PROCEED model for behavioral change. RESULTS: Thirty-eight participants in six focus groups identified nine environmental factors, 21 negative factors, and 14 positive factors pertaining to recognition and management of pediatric sepsis. These findings were organized into the PRECEDE-PROCEED planning model. Pediatric sepsis guidelines were identified as positive factors when they did exist and negative factors when they were complicated or did not exist. Six interventions were identified by participants. These include raising awareness of pediatric sepsis, increasing pediatric education, receiving feedback on prehospital encounters, increasing pediatric exposure and skills training, and improving dispatch information. CONCLUSION: This study fills a gap by examining barriers and facilitators to prehospital diagnosis and management of pediatric sepsis. Using the PRECEDE-PROCEED model, nine environmental factors, 21 negative factors, and 14 positive factors were identified. Participants identified six interventions that could create the foundation to improve prehospital pediatric sepsis care. Policy changes were suggested by the research team based on the results of this study. These interventions and policy changes provide a roadmap for improving care in this population and lay the groundwork for future research.

Implementation of an Automated Sepsis Screening Tool in a Children's Hospital Emergency Department: A Cost Analysis.

OBJECTIVE: To determine the effect of implementation of an automated sepsis screening tool on the median cost of affected patient encounters. STUDY DESIGN: This retrospective cohort study used propensity score-matched comparison groups to assess the difference in median cost for comparable affected patient encounters before and after the implementation of an automated sepsis screening tool in a large US children's hospital emergency department (ED) with >90 000 annual visits. All patient encounters in 2018 impacted by the automated sepsis screening tool were included and compared with a propensity score-matched comparison group drawn from patient encounters in 2012 that might have been affected by the screening tool had it been active at that time. The main outcome was the change in the median cost for comparable affected patient encounters. RESULTS: The overall median cost for those affected by an automated sepsis screening tool decreased by 21.2%, from $6454 (IQR, $968-$21 697) to $5084 (IQR, $802-$16 618). The median cost for encounters with an associated International Classification of Diseases sepsis code decreased by 51.1%, from $58 685 (IQR, $32 224-$134 895) to $28 672 (IQR, $16 796-$60 657). CONCLUSIONS: The median cost for comparable patient encounters decreased with implementation of an automated sepsis screening tool in the pediatric ED. Costs were decreased even more substantially for patients with sepsis. In addition to improving outcomes, an automated sepsis screening tool appears to be at least cost-effective and may be cost-saving, an incentive for more widespread use of this technology.

Association Between the First-Hour Intravenous Fluid Volume and Mortality in Pediatric Septic Shock.

STUDY OBJECTIVE: To determine whether the receipt of more than or equal to 30 mL/kg of intravenous fluid in the first hour after emergency department (ED) arrival is associated with sepsis-attributable mortality among children with hypotensive septic shock. METHODS: This is a retrospective cohort study set in 57 EDs in the Improving Pediatric Sepsis Outcomes quality improvement collaborative. Patients less than 18 years of age with hypotensive septic shock who received their first intravenous fluid bolus within 1 hour of arrival at the ED were propensity-score matched for probability of receiving more than or equal to 30 mL/kg in the first hour. Sepsis-attributable mortality was compared. We secondarily evaluated the association between the first-hour fluid volume and sepsis-attributable mortality in all children with suspected sepsis in the first hour after arrival at the ED, regardless of blood pressure. RESULTS: Of the 1,982 subjects who had hypotensive septic shock and received a first fluid bolus within 1 hour of arrival at the ED, 1,204 subjects were propensity matched. In the matched patients receiving more than or equal to 30 mL/kg of fluid, 26 (4.3%) of 602 subjects had 30-day sepsis-attributable mortality compared with 25 (4.2%) of 602 receiving less than 30 mL/kg (odds ratio 1.04, 95% confidence interval 0.59 to 1.83). Among the patients with suspected sepsis regardless of blood pressure, 30-day sepsis-attributable mortality was 3.0% in those receiving more than or equal to 30 mL/kg versus 2.0% in those receiving less than 30 ml/kg (odds ratio 1.52, 95% confidence interval 0.95 to 2.44.) CONCLUSION: In children with hypotensive septic shock receiving a timely first fluid bolus within the first hour of ED care, receiving more than or equal to 30 mL/kg of bolus intravenous fluids in the first hour after arrival at the ED was not associated with mortality compared with receiving less than 30 mL/kg.

Comparison of children receiving emergent sepsis care by mode of arrival.

OBJECTIVE: To determine if differences in patient characteristics, treatments, and outcomes exist between children with sepsis who arrive by emergency medical services (EMS) versus their own mode of transport (self-transport). METHODS: Retrospective cohort study of patients who presented to the Emergency Department (ED) of two large children's hospitals and treated for sepsis from November 2013 to June 2017. Presentation, ED treatment, and outcomes, primarily time to first bolus and first parental antibiotic, were compared between those transported via EMS versus patients who were self-transported. RESULTS: Of the 1813 children treated in the ED for sepsis, 1452 were self-transported and 361 were transported via EMS. The EMS group were more frequently male, of black race, and publicly insured than the self-transport group. The EMS group was more likely to have a critical triage category, receive initial care in the resuscitation suite (51.9 vs. 22%), have hypotension at ED presentation (14.4 vs. 5.4%), lactate >2.0 mmol/L (60.6 vs. 40.8%), vasoactive agents initiated in the ED (8.9 vs. 4.9%), and to be intubated in the ED (14.4 vs. 2.8%). The median time to first IV fluid bolus was faster in the EMS group (36 vs. 57 min). Using Cox LASSO to adjust for potential covariates, time to fluids remained faster for the EMS group (HR 1.26, 95% CI 1.12, 1.42). Time to antibiotics, ICU LOS, 3- or 30-day mortality rates did not differ, yet median hospital LOS was significantly longer in those transported by EMS versus self-transported (6.5 vs. 5.3 days). CONCLUSIONS: Children with sepsis transported by EMS are a sicker population of children than those self-transported on arrival and had longer hospital stays. EMS transport was associated with earlier in-hospital fluid resuscitation but no difference in time to first antibiotic. Improved prehospital recognition and care is needed to promote adherence to both prehospital and hospital-based sepsis resuscitation benchmarks.

Coming Together to Save Babies: Our Institution's Quality Improvement Collaborative to Improve Infant Safe Sleep Practices.

Many hospitalized infants are not observed in an American Academy of Pediatrics-recommended safe sleep environment, which can translate to unsafe sleep practices at home. We implemented this collaborative to reduce our county's sleep-related death rate by improving infant safe sleep practices in the freestanding children's hospital setting and increasing safe sleep screening and education in our clinics and emergency departments (EDs). METHODS: Physicians from our institution's primary care clinics, EDs, neonatal intensive care units, and general inpatient units created and led multidisciplinary safe sleep teams. Teams have used standardized data tools to collect information on infant patient ages and sleep position and environment, both in the hospital and at home. Based on audit data, teams have implemented multiple Plan-Do-Study-Act cycles during this collaborative. We have calculated changes in safe sleep practices in the hospital and changes in screening and education on safe sleep behaviors over time. RESULTS: Our teams have significantly increased compliance with safe sleep practices in the inpatient and neonatal intensive care unit settings (P < 0.01). We have also increased screening and education on appropriate safe sleep behaviors by ED and primary care providers (P < 0.01). Our county's sleep-related death rate has not significantly decreased during the collaborative. CONCLUSIONS: Our collaborative has increased American Academy of Pediatrics-recommended safe sleep practices in our institution, and we decreased sleep-related deaths in our primary care network. We have created stronger ties to our community partners working to decrease infant mortality rates. More efforts will be needed, both within and outside of our institution, to lower our community's sleep-related death rate.

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma.

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

Automating a Manual Sepsis Screening Tool in a Pediatric Emergency Department.

OBJECTIVE: This article describes the method of integrating a manual pediatric emergency department sepsis screening process into the electronic health record that leverages existing clinical documentation and keeps providers in their current, routine clinical workflows. METHODS: Criteria in the manual pediatric emergency department sepsis screening tool were mapped to standard documentation routinely entered in the electronic health record. Data elements were extracted and scored from the medical history, medication record, vital signs, and physical assessments. Scores that met a predefined sepsis risk threshold triggered interruptive system alerts which notified emergency department staff to perform sepsis huddles and consider appropriate interventions. Statistical comparison of the new electronic tool to the manual process was completed by a two-tail paired t-test. RESULTS: The performance of the pediatric electronic sepsis screening tool was evaluated by comparing flowsheet row documentation of the manual, sepsis alert process against the interruptive system alert instance of the electronic sepsis screening tool. In an 8-week testing period, the automated pediatric electronic sepsis screening tool identified 100% of patients flagged by the manual process (n = 29), on average, 68 minutes earlier. CONCLUSION: Integrating a manual sepsis screening tool into the electronic health record automated identification of pediatric sepsis screening in a busy emergency department. The electronic sepsis screening tool is as accurate as a manual process and would alert bedside clinicians significantly earlier in the emergency department course. Deployment of this electronic tool has the capability to improve timely sepsis detection and management of patients at risk for sepsis without requiring additional documentation by providers.

Lethal aggression in Pan is better explained by adaptive strategies than human impacts.

Observations of chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) provide valuable comparative data for understanding the significance of conspecific killing. Two kinds of hypothesis have been proposed. Lethal violence is sometimes concluded to be the result of adaptive strategies, such that killers ultimately gain fitness benefits by increasing their access to resources such as food or mates. Alternatively, it could be a non-adaptive result of human impacts, such as habitat change or food provisioning. To discriminate between these hypotheses we compiled information from 18 chimpanzee communities and 4 bonobo communities studied over five decades. Our data include 152 killings (n = 58 observed, 41 inferred, and 53 suspected killings) by chimpanzees in 15 communities and one suspected killing by bonobos. We found that males were the most frequent attackers (92% of participants) and victims (73%); most killings (66%) involved intercommunity attacks; and attackers greatly outnumbered their victims (median 8:1 ratio). Variation in killing rates was unrelated to measures of human impacts. Our results are compatible with previously proposed adaptive explanations for killing by chimpanzees, whereas the human impact hypothesis is not supported.

Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors.

Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.

Identification and optimisation of a series of substituted 5-pyridin-2-yl-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors.

Further investigation of a series of thienyl-based hydroxamic acids that included ADS100380 and ADS102550 led to the identification of the 5-pyridin-2-yl-thiophene-2-hydroxamic acid 3c, which possessed modest HDAC inhibitory activity. Substitution at the 5- and 6-positions of the pyridyl ring of compound 3c provided compounds 5a-g, 7a, b, 9, and 13a. Compound 5b demonstrated improved potency, in vitro DMPK profile, and rat oral bioavailability, compared to ADS102550. Functionalisation of the pendent phenyl group of compounds 5b, 5e and 13a provided analogues that possessed excellent enzyme inhibition and anti-proliferative activity.

Identification of early-stage colorectal cancer patients at risk of relapse post-resection by immunobead reverse transcription-PCR analysis of peritoneal lavage fluid for malignant cells.

PURPOSE: Colorectal cancer patients diagnosed with stage I or II disease are not routinely offered adjuvant chemotherapy following resection of the primary tumor. However, up to 10% of stage I and 30% of stage II patients relapse within 5 years of surgery from recurrent or metastatic disease. The aim of this study was to determine if tumor-associated markers could detect disseminated malignant cells and so identify a subgroup of patients with early-stage colorectal cancer that were at risk of relapse. EXPERIMENTAL DESIGN: We recruited consecutive patients undergoing curative resection for early-stage colorectal cancer. Immunobead reverse transcription-PCR of five tumor-associated markers (carcinoembryonic antigen, laminin gamma2, ephrin B4, matrilysin, and cytokeratin 20) was used to detect the presence of colon tumor cells in peripheral blood and within the peritoneal cavity of colon cancer patients perioperatively. Clinicopathologic variables were tested for their effect on survival outcomes in univariate analyses using the Kaplan-Meier method. A multivariate Cox proportional hazards regression analysis was done to determine whether detection of tumor cells was an independent prognostic marker for disease relapse. RESULTS: Overall, 41 of 125 (32.8%) early-stage patients were positive for disseminated tumor cells. Patients who were marker positive for disseminated cells in post-resection lavage samples showed a significantly poorer prognosis (hazard ratio, 6.2; 95% confidence interval, 1.9-19.6; P = 0.002), and this was independent of other risk factors. CONCLUSION: The markers used in this study identified a subgroup of early-stage patients at increased risk of relapse post-resection for primary colorectal cancer. This method may be considered as a new diagnostic tool to improve the staging and management of colorectal cancer.

Detection of occult metastasis in lymph nodes from colorectal cancer patients: a multiple-marker reverse transcriptase-polymerase chain reaction study.

INTRODUCTION: Lymph node status is a key factor for disease staging and is the main determinant for adjuvant therapy of colorectal cancer. The current staging procedure is unable to identify occult metastasis in lymph nodes, which is likely to be an important cause of treatment failure in some early-stage patients. The detection of occult metastasis could identify a patient subgroup at risk for disease relapse that would benefit from adjuvant therapy. The purpose of this study was to establish and test a multimarker reverse transcriptase-polymerase chain reaction assay for the molecular detection of occult metastases in lymph nodes. METHODS: Forty-four patients with colorectal cancer and 14 patients with benign bowel diseases undergoing colonic resection were enrolled in the study. Reverse transcriptase-polymerase chain reaction was used to detect expression of three epithelial markers, carcinoembryonic antigen, cytokeratin 20, and guanylyl cyclase C, in fresh colorectal lymph node tissue. RESULTS: Forty-six of 47 (97.9 percent) histologically positive lymph nodes were also positive by reverse transcriptase-polymerase chain reaction. Of 221 histologically negative nodes, 97 (43.9 percent) were positive for at least one of the three markers by reverse transcriptase-polymerase chain reaction: 24.9 percent for carcinoembryonic antigen, 16.7 percent for cytokeratin 20, and 24.9 percent for guanylyl cyclase C. Among these were 13 of 20 stage I and II cases, implying a staging shift to stage III by molecular diagnosis of occult metastasis. Fifty-nine additional nodes were found to be positive for occult metastases in 22 of 24 stage III and IV patients. CONCLUSIONS: These results indicate that occult metastases are detectable by reverse transcriptase-polymerase chain reaction in histologically negative lymph nodes from colorectal cancer. The use of a panel of three markers improves the specificity of the method.