Metabolomics and Inflammatory Mediator Profiling for the Differentiation of Life-Threatening and Non-Severe Appendicitis in the Pediatric Population.

While children with appendicitis often have excellent clinical outcomes, some develop life-threatening complications including sepsis and organ dysfunction requiring pediatric intensive care unit (PICU) support. Our study applied a metabolomics and inflammatory protein mediator (IPM) profiling approach to determine the bio-profiles of children who developed severe appendicitis compared with those that did not. We performed a prospective case-control study of children aged 0-17 years with a diagnosis of appendicitis. Cases had severe disease resulting in PICU admission. Primary controls had moderate appendicitis (perforation without PICU); secondary controls had mild appendicitis (non-perforated). Serum samples were analyzed using Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy and Gas Chromatography-Mass Spectrometry (GC-MS); IPM analysis was performed using plasma bead-based multiplex profiling. Comparisons were made using multivariate data statistical analysis. Fifty-three children were included (15 severe, 38 non-severe). Separation between severe and moderate appendicitis demonstrated excellent sensitivity and specificity (100%, 88%; 14 compounds), separation between severe and mild appendicitis also showed excellent sensitivity and specificity (91%, 90%; 16 compounds). Biomarker patterns derived from metabolomics and IPM profiling are capable of distinguishing children with severe appendicitis from those with less severe disease. These findings provide an important first step towards developing non-invasive diagnostic tools for clinicians in early identification of children who are at a high risk of developing severe appendicitis.

Magnetic Resonance Imaging Provides Useful Diagnostic Information Following Equivocal Ultrasound in Children With Suspected Appendicitis [Formula: see text].

PURPOSE: In Canada, ultrasonography is the primary imaging modality for children with suspected appendicitis, yet equivocal studies are common. Magnetic resonance imaging provides promise as an adjunct imaging strategy. The primary objective of this study was to determine the proportion of children with suspected appendicitis and equivocal ultrasound where magnetic resonance imaging determined a diagnosis. METHODS: A prospective consecutive cohort of children aged 5-17 years presenting to a tertiary pediatric Emergency Department with suspected appendicitis were enrolled. Participants underwent diagnostic and management strategies according to our local suspected appendicitis pathway, followed by magnetic resonance (Siemens Avanto 1.5 Tesla) imaging. Sub-specialty pediatric radiologists reported all images. RESULTS: Magnetic resonance imaging was performed in 101 children with suspected appendicitis. The mean age was 11.9 (SD 3.4) years and median Pediatric Appendicitis Score was 6 [IQR 4,8]. Ultrasonography was completed in 98/101 (97.0%). Of 53/98 (54.1%) with equivocal ultrasound, magnetic resonance imaging provided further diagnostic information in 41 (77.4%; 10 positive, 31 negative; 12 remained equivocal). Secondary findings of appendicitis on magnetic resonance imaging in children with equivocal ultrasound included abdominal free fluid (24, 45.3%), peri-appendiceal fluid (12, 22.6%), intraluminal appendiceal fluid (9, 17.0%), fat stranding (8, 15.1%), appendicolith (2, 3.8%), and peri-appendiceal abscess (1, 1.9%). The observed agreement between magnetic resonance imaging results and final diagnosis was 94.9% (kappa = 0.89).

Optimizing postoperative follow-up in pediatric surgery (OFIPS).

BACKGROUND/PURPOSE: The purpose of the study was to determine variables associated with attending postoperative clinic follow-up (POFU) in pediatric surgical patients, predictors of clinical value, and visit cost estimates. METHODS: POFU patterns of children undergoing eight common pediatric surgical procedures over one year at a tertiary pediatric hospital were examined retrospectively. Variables associated with attending POFU and associated with predetermined measures of clinical value and cost were determined. Driving distance to hospital was chosen as a proxy measure of cost to the family. RESULTS: Six-hundred-thirty-three patients were included, and 58% attended POFU. Variables independently associated with attending follow-up included: procedure type (orchidopexy, complicated appendicitis), living close to the hospital, having a defined follow-up order, individual surgeon attending. Clinical value was identified in 16.4% of patient visits and associated with orchidopexies, having required an earlier urgent postoperative visit and longer cases considered "complex". Significant costs to the health care system (~$125,000) and families (~$15,000) could be estimated from follow-up cases that had no clinical issues identified nor required an intervention. CONCLUSION: POFU of common pediatric surgical procedures may have limited clinical value while coming at significant costs to families and the health care system. Further study is needed to define optimal needs and means of follow-up of these common pediatric surgical procedures. LEVEL OF EVIDENCE: Level III.

The Use of Metabolomics and Inflammatory Mediator Profiling Provides a Novel Approach to Identifying Pediatric Appendicitis in the Emergency Department.

Multiplexed profiling approaches including various 'omics' platforms are becoming a new standard of biomarker development for disease diagnosis and prognosis. The present study applied an integrated metabolomics and cytokine profiling approach as a potential aid to the identification of pediatric appendicitis. Metabolic analysis using serum (n = 121) and urine (n = 102) samples, and cytokine analysis using plasma (n = 121) samples from children presenting to the Emergency Department with abdominal pain were performed. Comparisons between children with appendicitis vs. non-appendicitis abdominal pain, and with perforated vs. non-perforated appendicitis were made using multivariate statistics. Serum and urine biomarker patterns were statistically significantly different between groups. The combined serum metabolomics and inflammatory mediator model revealed clear separation between appendicitis and non-appendicitis abdominal pain (AUROC: 0.92 ± 0.03) as well as for perforated and non-perforated appendicitis (AUROC: 0.88 ± 0.05). Urine metabolic analysis also demonstrated distinction between the groups appendicitis and non-appendicitis abdominal pain (AUROC: 0.85 ± 0.04), and perforated and non-perforated appendicitis (AUROC: 0.98 ± 0.02). In children presenting to the Emergency Department with abdominal pain, metabolomics and inflammatory mediator profiling are capable of distinguishing children with appendicitis from those without. The approach also differentiates between severities of disease. These results provide an important first step towards a potential aid for improving appendicitis identification.

The Use of Routine Blood Cultures in Pediatric Appendicitis.

OBJECTIVES: To determine the proportion of true-positive blood culture results in children presenting to the ED with suspected appendicitis. To describe the current practice of obtaining blood cultures in children with suspected appendicitis. METHODS: We performed a 2-year retrospective health record review of all children aged 2 through 17 years investigated for suspected appendicitis at a tertiary Pediatric Emergency Department. Subjects were identified by searching (a) institutional records for ICD-10-CA coding, (b) diagnostic imaging records of ultrasounds for appendicitis, and (c) surgical database records for nonincidental appendectomies. Abstracted demographic and clinical data were matched to regional laboratory services data to describe the performance and result of blood cultures. RESULTS: Overall, 1315 children investigated for appendicitis were reviewed. Seven hundred fifty (57.0%) were girls, the average age was 11.7 years (SD, 4.0). Blood cultures were obtained in 288 (21.9%) of 1315 patients. Of the 11 (3.8%) cultures that were positive, only 1 (0.35%) was a true positive. Young age, high triage acuity, and presence of fever were associated with the acquisition of cultures (P < 0.001 for all). The proportion of children undergoing appendectomy and the negative appendectomy rate was similar between those with and without blood culture (P = 0.10 and P = 0.96, respectively). CONCLUSIONS: True-positive blood cultures are very rare in children presenting to the ED with suspected appendicitis. Given the potential for false-positive cultures and the social/economic implications of initial testing/retesting of false positives, the use of routine blood cultures for children with suspected appendicitis is not supported.

Test characteristics of common appendicitis scores with and without laboratory investigations: a prospective observational study.

BACKGROUND: Despite the poor independent test characteristics of the white blood cell count (WBC) and neutrophil count (NC) in identifying appendicitis, common clinical decision supports including the Pediatric Appendicitis Score (PAS) and Alvarado Score (AS), require the WBC and NC values. Moreover, blood tests cause discomfort/pain to children and require time for processing results. Scores based on clinical information alone may be of benefit in the pediatric population. The objective of our study was to determine the test characteristics of the PAS and the AS with and without laboratory investigations (mPAS, mAS respectively) as well as the Lintula Score. METHODS: A prospective cohort study of children aged 5-17 years presenting to a pediatric ED with suspected appendicitis. Clinical care of the patient was left to the managing physician. At risk for appendicitis was defined by PAS ≥6; AS ≥5; LS ≥16, as originally described; modified cutoffs were defined as mPAS ≥4; mAS ≥4. Appendicitis was defined as acute inflammation, rupture or abscess of the appendix on pathologic evaluation. Test characteristics for each of the 5 scores were calculated. RESULTS: Of the 180 eligible children, 102 (56.7 %) were female. The average age was 11.2 years (SD 3.1). Appendectomy was performed in 58 (32.2 %) of children, 55 (94.8 %) were positive. For the PAS and mPAS, sensitivity and negative predictive values were similar (80.0 %, 86.4 % vs 87.3 %, 85.1 % respectively). For the AS and mAS, sensitivity and negative predictive values were also similar (85.5 %, 87.1 % vs 83.6 %, 83.3 % respectively). Specificities in the PAS, mPAS, AS and mAS were low (56.0 %, 32.0 %, 43.2 %, 63.0 % respectively). Test characteristics of the LS were poor (59.3 %, 79.2 %, 55.2 %, 81.8 %). CONCLUSIONS: A modified Alvarado and PAS can be used to screen for children at low risk of appendicitis who may be carefully observed at home without the need for laboratory investigation. Translation to primary care settings should evaluate generalizability and determine impact on referral patterns.

The Effect of a Full Bladder on Proportions of Diagnostic Ultrasound Studies in Children with Suspected Appendicitis.

OBJECTIVES: We examined the effect of a full bladder on proportions of diagnostic ultrasound (US) studies in children with suspected appendicitis. We also examined the effect of a full bladder on proportions of fully visualized ovaries on US in children with suspected appendicitis. METHODS: We conducted a retrospective health record review of children aged 2-17 years presenting to a tertiary pediatric emergency department (ED) with suspected appendicitis who had an ultrasound performed. We compared proportions of diagnostic US studies in children with full and sub-optimally filled bladders. We also compared proportions of ovarian visualization in females with full and sub-optimally filled bladders. RESULTS: 678 children were included in our final analysis. The proportion of diagnostic US studies did not vary significantly between groups with a full (132/283, 47%, 95% confidence interval [CI] 38%-56%) or sub-optimally filled bladder (205/395, 52%, 95% CI 47%-57%)(p=0.17). Rates of ovarian visualization were higher in females with a full bladder (196/205, 96%, 95% CI 93%-99%) compared to those with a sub-optimally filled bladder (180/223, 81%, 95% CI 76%-86%) (p<0.01). CONCLUSIONS: Administrators and clinical decision makers should consider removing routine bladder filling practice from current pediatric appendicitis protocols in males and in pre-pubertal females where ovarian pathology is not suspected. Selective bladder filling prior to US should be performed in females when ovarian pathology is suspected.

Implementation of an Advanced Nursing Directive for Children With Right Lower Quadrant Pain: Identifying Those Requiring Further Investigation and Improving Flow Metrics.

OBJECTIVES: Advanced nursing directives (ANDs) empower nursing staff to provide advanced levels of care before physician assessment. The objectives of this study were (1) to determine whether an AND for right lower quadrant (RLQ) pain could identify children who required any further investigation to diagnose appendicitis and (2) to determine whether children meeting AND criteria had better emergency department (ED) flow metrics compared with those who did not meet the criteria. METHODS: Health records of children aged 3 to 17 years presenting to the ED with abdominal pain who were managed using the departmental AND for RLQ pain were reviewed. Primary outcomes included (1) the proportion of patients requiring further investigation to diagnose appendicitis and (2) the time interval from triage to blood draw. Secondary outcomes included additional ED flow metrics, perforation rate, and negative appendectomy rate. RESULTS: An AND was completed for 210 children. Those who met the AND criteria were more likely to undergo further investigation to rule out appendicitis than those who did not meet the criteria (92/137 [67.2%] vs 32/73 [43.8%]; odds ratio [OR], 2.62; 95% confidence interval [CI], 1.40-4.90). Time to blood draw was significantly lower for those children meeting the AND criteria (74 vs 162 minutes, P < 0.001) as was time to hospital admission (271 vs 395 minutes, P = 0.008) and appendectomy (498 vs 602 minutes, P = 0.015). The negative appendectomy rate was 8.6% (5/58) for children meeting the AND criteria and 9.1% (2/22) for those not meeting the criteria (OR, 0.94; 95% CI, 0.14-10.67); the perforation rate was 29.3% (17/58) and 4.5% (1/22), respectively (OR, 8.17; 95% CI, 1.17-380.86). CONCLUSIONS: Children presenting to the ED with RLQ pain who meet the AND criteria are more likely to require further investigation to rule out appendicitis and have better department flow metrics than those who do not meet the criteria. Our results provide further evidence of the utility of ANDs in the ED.

Variation in the Diagnosis and Management of Appendicitis at Canadian Pediatric Hospitals.

OBJECTIVES: The objective was to characterize the variations in practice in the diagnosis and management of children admitted to hospitals from Canadian pediatric emergency departments (EDs) with suspected appendicitis, specifically the timing of surgical intervention, ED investigations, and management strategies. METHODS: Twelve sites participated in this retrospective health record review. Children aged 3 to 17 years admitted to the hospital with suspected appendicitis were eligible. Site-specific demographics, investigations, and interventions performed were recorded and compared. Factors associated with after-hours surgery were determined using generalized estimating equations logistic regression. RESULTS: Of the 619 children meeting eligibility criteria, surgical intervention was performed in 547 (88%). After-hours surgery occurred in 76 of the 547 children, with significant variation across sites (13.9%, 95% confidence interval = 7.1% to 21.6%, p < 0.001). The overall perforation rate was 17.4% (95 of 547), and the negative appendectomy rate was 6.8% (37 of 547), varying across sites (p = 0.004 and p = 0.036, respectively). Use of inflammatory markers (p < 0.001), blood cultures (p < 0.001), ultrasound (p = 0.001), and computed tomography (p = 0.001) also varied by site. ED administration of narcotic analgesia and antibiotics varied across sites (p < 0.001 and p = 0.001, respectively), as did the type of surgical approach (p < 0.001). After-hours triage had a significant inverse association with after-hours surgery (p = 0.014). CONCLUSIONS: Across Canadian pediatric EDs, there exists significant variation in the diagnosis and management of children with suspected appendicitis. These results indicate that the best diagnostic and management strategies remain unclear and support the need for future prospective, multicenter studies to identify strategies associated with optimal patient outcomes.

Outcomes of children with suspected appendicitis and incompletely visualized appendix on ultrasound.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.