Implementing Nonoperative Treatment Strategy for Simple Pediatric Appendicitis: A Qualitative Study.

INTRODUCTION: A nonoperative treatment strategy (NOT) with antibiotics for children with simple appendicitis could reduce anesthesia and surgery-related complications. As the implementation of a new treatment in routine clinical practice may take years, this study aims to identify barriers and facilitators for implementation of NOT for children with simple appendicitis. MATERIALS AND METHODS: To identify barriers and facilitators for its implementation, we conducted 14 semistructured interviews and a focus group with health insurance/hospital policymakers, surgical clinicians, and young people-together with their parents-who have been treated surgically or with antibiotics. Transcripts were open coded and categorized as per the framework for healthcare innovations by Fleuren et al. RESULTS: We identified four main themes: (1) Appendicitis is a well-known disease. Children, parents, and clinicians regard appendectomy as routine and safe, making them reluctant toward other treatment options. (2) Clinicians regard uptake of NOT in the national appendicitis guideline necessary for its implementation. (3) For identification of patients best suited for NOT more experience and scientific evidence is needed. (4) Appendectomy and NOT have different risk and benefits making the treatment choice depended on individual patient preferences. CONCLUSIONS: By addressing how NOT and operative treatment are regarded by patients and surgeons could have a substantial impact on the implementation of NOT for children with simple appendicitis. Furthermore, the individual preferences of patients need to be taken into account when choosing between operative and NOT. In other words, offering NOT in a shared decision-making model seems the first appropriate step in its implementation.

International Core Outcome Set for Acute Simple Appendicitis in Children: Results of a Systematic Review, Delphi Study, and Focus Croups With Young People.

OBJECTIVE: To develop an international core outcome set (COS), a minimal collection of outcomes that should be measured and reported in all future clinical trials evaluating treatments of acute simple appendicitis in children. SUMMARY OF BACKGROUND DATA: A previous systematic review identified 115 outcomes in 60 trials and systematic reviews evaluating treatments for children with appendicitis, suggesting the need for a COS. METHODS: The development process consisted of 4 phases: (1) an updated systematic review identifying all previously reported outcomes, (2) a 2-stage international Delphi study in which parents with their children and surgeons rated these outcomes for inclusion in the COS, (3) focus groups with young people to identify missing outcomes, and (4) international expert meetings to ratify the final COS. RESULTS: The systematic review identified 129 outcomes which were mapped to 43 unique outcome terms for the Delphi survey. The first-round included 137 parents (8 countries) and 245 surgeons (10 countries), the second-round response rates were 61% and 85% respectively, with 10 outcomes emerging with consensus. After 2 young peoples' focus groups, 2 additional outcomes were added to the final COS (12): mortality, bowel obstruction, intraabdominal abscess, recurrent appendicitis, complicated appendicitis, return to baseline health, readmission, reoperation, unplanned appendectomy, adverse events related to treatment, major and minor complications. CONCLUSION: An evidence-informed COS based on international consensus, including patients and parents has been developed. This COS is recommended for all future studies evaluating treatment ofsimple appendicitis in children, to reduce heterogeneity between studies and facilitate data synthesis and evidence-based decision-making.

Outcomes after appendectomy in children with acute appendicitis treated at a tertiary paediatric centre: results from a retrospective cohort study.

PURPOSE: In general, an appendectomy is presumed to have a limited burden of disease. However, in current literature, reported complication rates vary. This study aims to provide additional insights in the incidence of post-appendectomy complications in children with acute appendicitis. METHODS: This retrospective cohort study included children (0-17 years old) that underwent appendectomy at our tertiary referral centre for suspected acute appendicitis (January 2011-December 2018). Children referred to our centre, and those that underwent non-operative treatment were excluded. Post-appendectomy complications were recorded from electronic medical charts using predefined definitions and classified as severe (Clavien-Dindo III-IV) or less severe (Clavien-Dindo I-II). RESULTS: A total of 131 children were included. Simple and complex appendicitis was diagnosed in 66 (50%) and 60 (46%) children, respectively. A non-inflamed appendix was seen in five (4%) children. One or more complications were identified in 33 (25%) patients. Eight (12%) children with simple appendicitis developed a complication, three of these were severe. In children with complex appendicitis, 23 (38%) children developed a complication, 14 of these were severe. CONCLUSION: This study shows a high rate of complications compared with current literature, both in children with simple and complex appendicitis. This is probably the result of our definition of complications and being a tertiary referral centre receiving more severe appendicitis cases. However, these results still show that appendectomy is not always a routine procedure with only few complications. Substantiating the need to keep optimizing treatment for children with appendicitis.

Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?

Investigator-initiated clinical trials are crucial for improving quality of care for children and pregnant women as they are often excluded from industry-initiated trials. However, trials have become increasingly time-consuming and costly since the EU Clinical Trial Directive entered into force in 2001. This directive made compliance with ICH-Good Clinical Practice Guidelines (ethical and quality standard for conducting human subject research) mandatory for all clinical trials, regardless of its risk-classification. By discussing two investigator-initiated, 'low-risk' drug trials, we aim to illustrate that compliance with all GCP requirements makes trials very laborious and expensive, while a clear rationale is missing. This discourages clinical researchers to start and carry out investigator-initiated research. However, the forthcoming EU Clinical Trial Regulation (No 536/2014) seems to provide a solution as it allows for less stringent rules for low-risk trials. We want to raise awareness for these developments in both the clinical research community and the European and national regulatory authorities. Implementation of this forthcoming Regulation regulatory policies should be done in such a way that investigator-initiated trials evaluating standard care interventions will become more feasible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research. What is Known • Investigator-initiated trials are indispensable for improving care for children and pregnant women as they are often excluded from industry-initiated trials • Trials have become increasingly time-consuming and costly because of mandatory compliance with ICH-GCP guidelines What is New • The forthcoming EU Clinical Trial Regulation allows less stringent rules for low-risk trials • The national legislator and regulatory authorities should recognize the importance of this opportunity and implement the Regulation in such a way that investigator-initiated trials will become more feasible.

Establishing a core outcome set for treatment of uncomplicated appendicitis in children: study protocol for an international Delphi survey.

INTRODUCTION: Appendicitis is a global disease affecting roughly 1 in every 12 people in the world, with the highest incidence between ages 10 and 19 years. To date, a wide variety of health outcomes have been reported in randomised controlled trials and meta-analyses evaluating treatments for appendicitis. This is especially the case in studies comparing non-operative treatment with operative treatment. A set of standard outcomes, to be reported in all future trials, is needed to allow for adequate comparison and interpretation of clinical trial results and to make data pooling possible. This protocol describes the development of such a global core outcome set (COS) to allow unified reporting of treatment interventions in children with acute uncomplicated appendicitis. METHODS AND ANALYSIS: We use current international standard methodology for the development and reporting of this COS. Its development consists of three phases: (1) an update of the most recent systematic review on outcomes reported in uncomplicated paediatric appendicitis research to identify additional outcomes, (2) a three-step global Delphi study to identify a set of core outcomes for which there is consensus between parents and (paediatric) surgeons and (3) an expert meeting to finalise the COS and its definitions. Children and young people will be involved through their parents during phase 2 and will be engaged directly using a customised face-to-face approach. ETHICS AND DISSEMINATION: The medical research ethics committee of the Academic Medical Center Amsterdam has approved the study. Each participating country/research group will ascertain ethics board approval. Electronic informed consent will be obtained from all participants. Results will be presented in peer-reviewed academic journals and at (international) conferences. TRIAL REGISTRATION NUMBER: COMET registration: 1119.

Clinical recovery in children with uncomplicated appendicitis undergoing non-operative treatment: secondary analysis of a prospective cohort study.

Non-operative treatment of uncomplicated appendicitis in children is gaining ground. Pending definitive evidence regarding its effectiveness, there is a call to evaluate clinical recovery after non-operative treatment. In this study, we analyzed data collected during initial admission of a multicenter prospective cohort in which children, 7-17 year, were treated non-operatively for uncomplicated appendicitis. During admission clinical parameters (pain and gastro-intestinal symptoms), inflammation parameters and sequential abdominal ultrasound were recorded. In total, 45 children were included, 42(93%) were discharged without the need for appendectomy; median [IQR] pain scores on admission were 5 [4-7], decreasing to 2 [0-3] after 1 day of treatment. Initially, 28/42 (67%) reported nausea and 19/42 (45%) vomiting; after 1 day, this was 3/42 (7%) and 1/42 (2%), respectively. White blood cell count declined from a median [IQR] of 12.9 [10.7-16.7] 10E9/L on admission to 7.0 [5.8-9.9] 10E9/L on day 1. Median [IQR] C-reactive protein levels increased from 27.5 [9-69] mg/L on admission to 48 [22-80] mg/L on day 1, declining to 21.5 [11-42] mg/L on day 2. Follow-up ultrasound showed no signs of complicated appendicitis in any of the patients.Conclusion: Clinical symptoms resolved in most children after 1 day of non-operative treatment. This suggests that non-operative treatment is a viable alternative to appendectomy regarding clinical recovery.Trail registration: NCT01356641 What is Known: • Non-operative treatment of uncomplicated appendicitis in children is safe and its use around the world is gaining ground, however high quality evidence from adequately designed randomized trials is still lacking. • Concerns have been raised regarding the potentially prolonged clinical recovery associated with non-operative treatment. What is New: • Most clinical symptoms resolve after 1 day of non-operative treatment in the majority of children.

Initial non-operative management of uncomplicated appendicitis in children: a protocol for a multicentre randomised controlled trial (APAC trial).

INTRODUCTION: Based on epidemiological, immunological and pathology data, the idea that appendicitis is not necessarily a progressive disease is gaining ground. Two types are distinguished: simple and complicated appendicitis. Non-operative treatment (NOT) of children with simple appendicitis has been investigated in several small studies. So far, it is deemed safe. However, its effectiveness and effect on quality of life (QoL) have yet to be established in an adequately powered randomised trial. In this article, we provide the study protocol for the APAC (Antibiotics versus Primary Appendectomy in Children) trial. METHODS AND ANALYSIS: This multicentre, non-inferiority, randomised controlled trial randomises children aged 7-17 years with imaging-confirmed simple appendicitis between appendectomy and NOT. Patients are recruited in 15 hospitals. The intended sample size, based on the primary outcome, rate of complications and a non-inferiority margin of 5%, is 334 patients.NOT consists of intravenous antibiotics for 48-72 hours, daily blood tests and ultrasound follow-up. If the patient meets the predefined discharge criteria, antibiotic treatment is continued orally at home. Primary outcome is the rate of complications at 1-year follow-up. An independent adjudication committee will assess all complications and their relation to the allocated treatment. Secondary outcomes include, but are not limited to, delayed appendectomies, QoL, pain and (in)direct costs.The primary outcome will be analysed both according to the intention-to-treat principle and the per-protocol principle, and is presented with a one-sided 97.5% CI. We will use multiple logistic and linear regression for binary and continuous outcomes, respectively, to adjust for stratification factors. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethics Review Committee of the Academic Medical Center, Amsterdam. Data monitoring is performed by an independent institute and a Data Safety Monitoring Board has been assigned. Results will be presented in peer-reviewed academic journals and at (international) conferences. TRIAL REGISTRATION NUMBER: NCT02848820; NTR5977; Pre-results.

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.

BACKGROUND & AIMS: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters. CONCLUSIONS: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).

Prevalence of left and balanced coronary arterial dominance decreases with increasing age of patients at autopsy. A postmortem coronary angiograms study.

BACKGROUND: In patients presenting with an acute coronary syndrome, left over right coronary dominance appears to be independently associated with increased long-term mortality. This could lead to decreasing numbers of patients with a left dominant coronary artery system in older age groups. METHODS: We assessed the type of coronary dominance in different age groups in postmortem angiograms that were routinely performed at autopsy between 1993 and 2007. Coronary dominance was determined by identifying the origin of the posterior descending artery and posterolateral branches on postmortem angiography. Age, gender, and cause of death were recorded from the autopsy database. The prevalence of left dominant, right dominant, and codominant systems was determined in three increasing age categories, with cutoffs based on tertiles. RESULTS: A total 1620 coronary angiograms were assessed; 167 were excluded because it was not possible to determine coronary dominance. The median age of all patients was 71 years; 56% were male. Of all deaths, 40% were classified as cardiac. Regarding coronary dominance, 81.2% was right, 9.1% was left, and 9.7% was codominant. Overall, a decrease in prevalence of left and codominant coronary systems was observed with increasing age in the three age cohorts (≤ 63 years, 64-75 years, and ≥ 76 years) (P=.001 for overall comparison). CONCLUSIONS: In this large autopsy cohort, the prevalence of a left dominant or codominant coronary system decreased with increasing age. These findings could relate to a slightly higher risk of mortality in case of left versus right coronary artery occlusion.