Importance Appendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery. Objective To provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population. Design, Setting, and Participants The Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children’s Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study. Exposure SA, PA, or nonappendicitis abdominal pain. Main Outcomes and Measures Blood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics. Results Seventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified. Conclusions This study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.
The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other patient representatives. The morning sessions focused on the impact of organ transplantation on patients' daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful.
Abstract Introduction The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician’s judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not. Methods We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2–17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis. Results Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability ( Q 2 ) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model ( Q 2 =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2–5 years old and 6–17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95 % confidence. Conclusions In children ages 2–17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort.
Objectives Despite a lack of evidence demonstrating superiority to non-steroidal anti-inflammatory drugs, like ketorolac, that are associated with lower risk of harms, opioids remain the most prescribed analgesic for acute abdominal pain. In this pilot trial, we will assess the feasibility of a definitive trial comparing ketorolac with morphine in children with suspected appendicitis. We hypothesise that our study will be feasible based on a 40% consent rate. Methods and analysis A single-centre, non-inferiority, blinded (participant, clinician, investigators and outcome assessors), double-dummy randomised controlled trial of children aged 6–17 years presenting to a paediatric emergency department with ≤5 days of moderate to severe abdominal pain (≥5 on a Verbal Numerical Rating Scale) and are investigated for appendicitis. We will use variable randomised blocks of 4–6 and allocate participants in 1:1 ratio to receive either intravenous (IV) ketorolac 0.5 mg/kg+IV morphine placebo or IV morphine 0.1 mg/kg+IV ketorolac placebo. Analgesic co-intervention will be limited to acetaminophen (commonly used as first-line therapy). Participants in both groups will be allowed rescue therapy (morphine 0.5 mg/kg) within 60 min of our intervention. Our primary feasibility outcome is the proportion of eligible patients approached who provide informed consent and are enrolled in our trial. Our threshold for feasibility will be to achieve a ≥40% consent rate, and we will enrol 100 participants into our pilot trial. Ethics and dissemination Our study has received full approval by the Hamilton integrated Research Ethics Board. We will disseminate our study findings at national and international paediatric research conferences to garner interest and engage sites for a future multicentre definitive trial. Trial registration NCT04528563 , Pre-results.
Objective Given the public health importance of suicide-related behaviors and the corresponding gap in the performance measurement literature, we sought to identify key candidate process indicators (quality of care measures) and structural measures (organizational resources and attributes) important for emergency department (ED) management of pediatric suicide-related behaviors. Methods We reviewed nationally endorsed guidelines and published research to establish an inventory of measures. Next, we surveyed expert pediatric ED clinicians to assess the level of agreement on the relevance (to patient care) and variability (across hospitals) of 42 candidate process indicators and whether 10 hospital and regional structural measures might impact these processes. Results Twenty-three clinicians from 14 pediatric tertiary-care hospitals responded (93% of hospitals contacted). Candidate process indicators identified as both most relevant to patient care (≥87% agreed or strongly agreed) and most variable across hospitals (≥78% agreed or strongly agreed) were wait time for medical assessment; referral to crisis intervention worker/program; mental health, psychosocial, or risk assessment requested; any inpatient admission; psychiatric inpatient admission; postdischarge treatment plan; wait time for first follow-up appointment; follow-up obtained; and type of follow-up obtained. Key hospital and regional structural measures (≥87% agreed or strongly agreed) were specialist staffing and type of specialist staffing in or available to the ED; regional policies, protocols, or procedures; and inpatient psychiatric services. Conclusions This study highlighted candidate performance measures for the ED management of pediatric suicide-related behaviors. The 9 candidate process indicators (covering triage, assessment, admission, discharge, and follow-up) and 4 hospital and regional structural measures merit further development.
Vaccines against COVID-19 are likely to be approved for children under 12 years in the near future. Understanding vaccine hesitancy in parents is essential for reaching herd immunity. A cross-sectional survey of caregivers in 12 emergency departments (ED) was undertaken in the U.S., Canada, and Israel. We compared reported willingness to vaccinate children against COVID-19 with an initial survey and post-adult COVID-19 vaccine approval. Multivariable logistic regression models were performed for all children and for those <12 years. A total of 1728 and 1041 surveys were completed in phases 1 and 2, respectively. Fewer caregivers planned to vaccinate against COVID-19 in phase 2 (64.5% and 59.7%, respectively; p = 0.002). The most significant positive predictor of willingness to vaccinate against COVID-19 was if the child was vaccinated per recommended local schedules. Fewer caregivers plan to vaccinate their children against COVID-19, despite vaccine approval for adults, compared to what was reported at the peak of the pandemic. Older caregivers who fully vaccinated their children were more likely to adopt vaccinating children. This study can inform target strategy design to implement adherence to a vaccination campaign.
The objective was to review the clinical outcomes of children with suspected appendicitis after an ultrasound (US) examination fails to fully visualize the appendix, the diagnostic characteristics of US in children with suspected appendicitis, and the predictive value of secondary signs of appendicitis when the appendix is not fully visualized. This was a retrospective health record review of children aged 3 to 17 years presenting to a tertiary pediatric emergency department (ED) with suspected appendicitis. Descriptive statistics and diagnostic test characteristics are reported. Overall, 968 children had US. The appendix was fully visualized in 442 cases (45.7%), and 526 (54.3%) children had incompletely visualized appendices. The disposition of those with incompletely visualized appendices were as follows: 59.1% were discharged home, 10.5% went directly to the operating room, and 30.4% were admitted to the hospital for further observation. Of those discharged home based on clinical findings after incompletely visualized appendices, fewer than 0.3% ended up having appendicitis. Ultimately 15.6% of children with incompletely visualized appendices had pathology-confirmed appendicitis. The sensitivity and specificity of US for children with fully visualized appendices were 99.5% (95% confidence interval [CI] = 96.7% to 100%) and 81.3% (95% CI = 75.2% to 86.2%), respectively. The sensitivity and specificity for the presence of any secondary sign in diagnosing appendicitis were 40.2% (95% CI = 29.6% to 51.7%) and 90.6% (95% CI = 87.5% to 93.2%), respectively. Children with incompletely visualized appendices on US can be safely discharged home based on clinical findings with an acceptable rate of missed appendicitis. Children with nonreassuring clinical examinations following incompletely visualized appendices on US may benefit from further imaging studies prior to appendectomy, to reduce the rate of negative appendectomy. While the presence of secondary signs of inflammation can be used to rule in appendicitis, statistical strength to rule out appendicitis in the absence of secondary signs is insufficient. Revisión de los resultados clínicos de los niños con sospecha de apendicitis tras un examen ecográfico fallido en la visualización completa del apéndice. Se revisaron también las características diagnósticas ecográficas en niños con sospecha de apendicitis, y el valor predictivo de los signos secundarios de apendicitis cuando el apéndice no es visualizado totalmente. Revisión retrospectiva de las historias clínicas de los niños entre 3 y 17 años que acudieron a un servicio de urgencias (SU) pediátrico de nivel terciario con sospecha de apendicitis. Se documentaron los estadísticos descriptivos y las características de las pruebas diagnósticas. A un total de 968 niños se les realizó una ecografía. El apéndice se visualizó completamente en 442 casos (45,7%), y en 526 (54.3%) de forma incompleta. La ubicación de aquéllos con una visualización incompleta ecográfica fue la siguiente: un 59,1% fueron dados de alta a domicilio, un 10,5% fue directamente al quirófano y un 30,4% fue ingresado en el hospital para mayor observación. Entre aquéllos dados de alta a domicilio en base a los hallazgos clínicos tras una visualización incompleta ecográfica, menos de un 0,3% acabaron teniendo una apendicitis. Finalmente, un 15,6% de los niños con visualización incompleta tuvo apendicitis confirmada anatomopatológicamente. La sensibilidad y la especificidad de la ecografía para niños con visualización completa del apéndice fuer on de un 99,5% (intervalo de confianza [IC] 95% = 96,7% a 100%), y un 81,3% (IC 95% = 75,2% a 86,2%), respectivamente. La sensibilidad y especificidad para la presencia de cualquier signo secundario en el diagnóstico de apendicitis fue ron de un 40,2% (IC 95% = 29,6% a 51,7%) y un 90,6% (IC 95% = 87,5% a 93,2%), respectivamente. Los niños con una visualización incompleta del apéndice en la ecografía pueden ser dados de alta al domicilio de forma segura basándose en los resultados clínicos con un porcentaje aceptable de apendicitis no diagnosticadas. Los niños con exploraciones clínicas no tranquilizadoras tras una visualización incompleta del apéndice en la ecografía pueden beneficiarse de otras pruebas de imagen previamente a la apendicectomía, para reducir el porcentaje de apendicectomias negativas. Mientras que la presencia de signos secundarios de inflamación puede utilizarse para diagnosticar la apendicitis, la potencia estadística para descartar la apendicitis en ausencia de signos secundarios es insuficiente. Although appendicitis is the most common nontraumatic pediatric surgical emergency,1, 2 children with appendicitis often lack classic historical and physical examination findings,3 making the diagnosis particularly challenging. While there is some evidence that delays in diagnosis and treatment make little difference in outcomes,4-6 some studies suggest treatment delays lead to increased rates of perforation,7 and treatment delayed for more than 36 hours may lead to a perforation rate as high as 65%.8 To improve diagnostic accuracy, imaging studies have been used with increasing frequency;9 however, significant limitations such as the ionizing radiation associated with computed tomography (CT) and reduced off-hours availability with ultrasound (US) exist.10 Different strategies have been proposed to optimize imaging in children with suspected appendicitis including US, CT, and staged protocols.11, 12 The local practice at our institution tends to rely on US as the primary mode of imaging in suspected appendicitis, combined with serial physical examinations. However, complete visualization of the appendix using US has recently been reported to range from 25% to 73%, leaving the clinician with a significant diagnostic conundrum.13 The objective of this study was to determine outcomes in children with suspected appendicitis who have incompletely visualized appendices on US. We also examined the frequency of incomplete visualization, the diagnostic accuracy of US when the appendix is visualized, and the predictive value of secondary signs of inflammation when the appendix is not visualized. We performed a retrospective descriptive health record review. This study was approved by the Conjoint Health Research Ethics Board of the University of Calgary. This study was conducted in the Departments of Pediatric Emergency Medicine (EM) and Pediatric Diagnostic Imaging at the Alberta Children's Hospital (ACH). We are a tertiary care facility serving southern Alberta, western Saskatchewan, and eastern British Columbia, with an annual ED census of approximately 72,000 visits and a catchment population of 1.8 million. Health records were reviewed for children aged 2 through 17 years old who underwent US for assessment of suspected appendicitis. Eligible subjects were identified using databases hosted by the Department of Diagnostic Imaging at the ACH. All potentially relevant charts were included in the review. Those children with imaging studies performed outside our institution were not included. To minimize the risk of missed cases, we also reviewed charts of all patients who underwent appendectomy. US examinations were performed by trained US technicians and reported by radiologists. Preliminary verbal reports are promptly available to the emergency physician (EP), and final readings are accessible electronically either immediately or the following morning. Data were collected for the defined inclusive time period of January 1, 2007, through December 31, 2008. Patients for whom complete data were not available were excluded from our final analysis. Full health records were reviewed and data were abstracted using a customized electronic data collection program (Filemaker Pro 11.0v4). We collected data on basic demographics, ED visit details, laboratory investigations, imaging studies, surgical considerations, disposition, and return visits to the ED. An incompletely visualized US was defined as any scan that failed to view the entire appendix. A borderline or equivocal US was defined as any report that included findings suggestive but not diagnostic of appendicitis and specifically included the terms "borderline" or "equivocal." A positive secondary sign for appendicitis was defined as any of the following: fat stranding, signs of abscess, enlarged prominent lymph nodes, or moderate or large free fluid in the right lower quadrant or pelvis. Physiologic, small, or trace free fluid alone were not considered secondary signs of inflammation. A normal appendix on the pathology report defined a negative appendectomy. Missed appendicitis was defined as a return visit to the emergency department (ED) within 2 weeks that resulted in an appendectomy with a confirmatory pathology report. Our primary outcomes were the ED disposition and the final diagnosis in children who had suspected appendicitis but incompletely visualized appendices on US. Secondary outcome measures included the test characteristics when the appendix was visualized; the diagnostic value of secondary signs when the appendix is not visualized; the proportion of patients undergoing CT scan, appendectomy, and negative appendectomy; and rate of missed appendicitis. Data from Filemaker Pro were exported to Microsoft Excel for Mac 2011. We extracted descriptive statistics from this data set, calculated nonadjusted odds ratios (OR) and 95% confidence intervals (CI) and used 2 × 2 tables to calculate sensitivity and specificity. A total of 1303 health records were reviewed and 968 children were included in the final analysis as outlined in Figure 1. Summary statistics and demographic data for our population are presented in Table 1. In the cohort of 526 children with incompletely visualized appendices, 55 (10.5%) went directly to the operating room from the ED, 160 (30.4%) were admitted to the ward for further observation, and 311 (59.1%) were discharged home. Of those discharged home 58 (18.6%) returned to the ED and two underwent subsequent appendectomy; one (0.3%) of these children had pathology-proven appendicitis, and the other had a normal appendix at pathology. Of those 160 admitted for further observation, 105 (65.6%) were discharged home; none had repeat visits. Fifty-five (34.4%) of these children had appendectomies after admission to the ward for serial examinations and 39 of those 55 had pathology-proven appendicitis. Data on secondary signs of inflammation were available in 520/526 patients with incompletely visualized appendices (Table 2). Appendicitis was significantly more likely in those with at least one secondary sign (OR = 6.52, 95% CI = 3.62 to 11.63). Seventy children (13.3%) had further imaging studies after their initial incompletely visualized US. Thirty-four (6.5%) children had repeat US (seven [21%] of these repeat scans fully visualized the appendix), and 36 (6.8%) children had CT scans. In the group of 442 children with fully visualized appendices, 232 (52.5%) scans were described as consistent with appendicitis, 175 (39.6%) were considered normal, and 35(7.9%) were considered borderline or equivocal. There were 40 false-positive scans defined by a negative appendectomy or discharge home with or without observation and no return visit to the ED. One patient had a false-negative US, was admitted for observation, and underwent an appendectomy with a positive pathology report. Excluding the 35 indeterminate and borderline scans, the sensitivity and specificity of US for children with fully visualized appendices were 99.5% (95% CI = 96.7% to 100%) and 81.3% (95% CI = 75.2% to 86.2%), respectively. In this retrospective cohort study, we have demonstrated that a significant number (15%) of children with incompletely visualized appendices on US have pathology-confirmed appendicitis. Given this large number, ED discharge of this population without further evaluation or subsequent reassuring serial examinations would seem unwise, potentially leading to a significant number of children with missed diagnoses and associated complications. Additional diagnostic strategies, such as further imaging studies or serial examinations, may mitigate the possibility of missed appendicitis in this population and should strongly be considered. In some cases a significant amount of time may pass between the initial decision to order an US and when the test is reported, affording the EP ample opportunity to perform repeat or serial examinations. This is particularly true at institutions where after-hours US performance is limited, due to either site-specific protocols (as in our case) or limited accessibility, leading to completion of the study the following morning. In this setting, serial examinations play an integral role in decision-making. It is likely that serial examinations demonstrating clinical improvement played a significant role in the disposition of the 60% of children who were discharged home in this study. In our cohort of patients, only one patient of 311 who were discharged home from the ED after incompletely visualized appendices on US was subsequently found to have pathology-proven appendicitis. While no data were collected on the specifics of serial examinations or duration of observation in the ED, our extremely low rate of missed appendicitis would suggest that discharging a patient based on clinical grounds after an incompletely visualized US is a safe practice. After an incompletely visualized appendix on US, if a patient's clinical picture remains concerning for appendicitis or deteriorates either in the ED or after serial observations on the ward, clinicians are left with a choice of further imaging studies (such as repeat US, CT, or magnetic resonance imaging [MRI]) or exploratory surgery. The risks and benefits of each option must be weighed. Our institution has intentionally focused on minimizing radiation exposure. As a result, our CT rate after incompletely visualized US (10 of 112) is significantly lower than at other institutions.11, 12 The strategy may come at the cost of operative risks and a higher negative appendectomy rate. In our cohort of all children undergoing appendectomy after US with incompletely visualized appendices, the negative appendectomy rate was 26.8%, which is significantly higher than those seen at other institutions (10% to 12%) where higher rates of CT are employed.11, 12 This suggests that in patients with incompletely visualized appendices who are clinically concerning enough to take to surgery, a liberalization of CT may reduce the number of negative appendectomies. Of course, such a reduction in negative appendectomies should be weighed against the significant risks of ionizing radiation in the pediatric population. In our study, reducing the rate of negative appendectomy from 26.8% to 10% would have prevented 19 negative appendectomies (30 vs. 11), at the cost of subjecting 112 patients to CT scanning (those going to surgery after incompletely visualized appendices on US). The number needed to image to reduce one negative appendectomy in this highly select group is 5.9 (112/19). An alternative to CT is repeat US. As the accuracy of US increases with increased duration of symptoms;14 after a period of observation a repeat US may provide additional information. In our study, 21% of children with repeat US had fully visualized appendices. In a study by Schuh and colleagues,15 36 of 39 children undergoing repeat US successfully ruled in or ruled out appendicitis. The utility of repeat US in suspected appendicitis is an area that requires further investigation. MRI is another modality that could be considered after an incompletely visualized appendix on US. In a retrospective case series, Herliczek et al.16 found that sensitivity and specificity of MRI for acute appendicitis in children with inconclusive US findings were 100 and 96%, respectively. Although MRI currently lacks the near-universal availability of US and CT, early studies16, 17 demonstrate excellent diagnostic accuracy and present a potential imaging option to avoid the risks of ionizing radiation associated with CT. We were able to obtain data on the presence of secondary signs in the vast majority (520 of 526) of our cases. The sensitivity and specificity for the presence of any secondary sign in diagnosing appendicitis were 40.2 and 90.6%, respectively. These results were similar to those found by Estey et al.18 and support their conclusion that although not commonly found, the presence of secondary signs of inflammation increases the likelihood of appendicitis. Excluding the 35 indeterminate and borderline scans, the sensitivity and specificity of US for children with fully visualized appendices were 99.5 and 81.3%, respectively. A recent prospective study13 with data from multiple tertiary care pediatric EDs demonstrated similar diagnostic accuracy of US when the appendix is fully visualized. Our study design was retrospective, which did not allow for follow-up of patients after discharge beyond screening for return ED visits. Some patients may have presented to other institutions and consequentially been misclassified, leading to a falsely low rate of missed appendicitis. However, our institution is the only pediatric tertiary care center in the region, patients are routinely instructed to return to our ED should concerns arise, and all children requiring surgical intervention are referred to our facility. While some strategies in the diagnosis and management of appendicitis may have changed since the time of our data collection, the core elements of our institutional appendicitis care plan have remained essentially the same, although generalizability to centers with alternate care processes may be limited. This study was conducted at a single center. US is an operator-dependent test, and the US technicians at our center may have different levels of training and experience than at other institutions. In addition, our analysis of secondary signs of inflammation was completed after initial health record review, and we were unable to obtain six US reports. Incompletely visualized appendices on ultrasound performed for suspected appendicitis in children can result in challenging decisions for clinicians. Based on our results, we conclude that physicians can safely discharge patients using their clinical judgment, with an acceptable rate of missed appendicitis (<0.3%). Children with nonreassuring clinical examinations following incompletely visualized appendices on ultrasound are likely to benefit from further imaging studies prior to appendectomy to reduce the rate of negative appendectomy. While the presence of secondary signs of inflammation can be used to rule in appendicitis, statistical strength in the absence of these signs is insufficient to rule out the diagnosis.
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