Identification of the Optimal Treatment Strategy for Complex Appendicitis in the Pediatric Population (CAPP)

The Identification of the Optimal Treatment Strategy for Complex Appendicitis in the Pediatric Population

Aim of this study is to evaluate the effect of different treatment strategies on overall complications, health related-Quality of Life (hr-QOL) and costs among two subtypes of complex appendicitis in children (<18 years old).

Main research questions: What is the difference in overall complications at three months between:

Subgroup 1 (complex appendicitis without abscess/mass formation): Laparoscopic (LA) and open appendectomy (OA) Subgroup 2: (complex appendicitis with abscess/mass formation): Non-operative treatment (NOT) and direct appendectomy

Study Overview

• Status: Recruiting
• Conditions: Appendicitis; Appendix Mass; Appendicitis Perforated
• Intervention / Treatment: Procedure: Laparoscopic appendectomy; Procedure: Open appendectomy; Procedure: Non-operative treatment; Procedure: Direct appendectomy

Detailed Description

Up till now initiated research projects worldwide mainly focus on simple appendicitis (questioning the necessity of an appendectomy). However, complex appendicitis is associated with significant morbidity (up to 30%), prolonged hospital stay and high costs. Identification of the optimal treatment strategy for children with complex appendicitis is therefore essential. Heterogeneity in the treatment of complex appendicitis still exists in daily practice and reflects the lack of high-quality data and emphasizes the need for well-designed studies. Complex appendicitis can be divided into two subtypes:

1. Complex appendicitis without mass/abscess. (subgroup 1) Although (inter)national guidelines agree that appendectomy should be usual care, the optimal approach (open or laparoscopy) is unclear. Laparoscopic appendectomy (LA) is increasingly applied both in adults (80%) and children (60%). Benefits reported for LA in children are, but not limited to, less superficial site infection (SSI), reduced length of hospital stay and significant less postoperative bowel obstruction compared with open appendectomy (OA). Reluctance for usage of LA in this specific subgroup, however, remains due to the potential higher incidence of post-appendectomy abscess formation (PAA) reported. However, the quality of studies on this topic is low and there is considerable inconsistency in results.
2. Complex appendicitis with mass/abscess. (subgroup 2) The recommendation made in our national guideline (to perform direct appendectomy in this subgroup) is not in line with the available literature. A recent Cochrane review on this topic could only include two trials and stated that no firm conclusions could be drawn. An older systematic review, including 7 studies in children, concluded that non-operative treatment (NOT) led to fewer complications, specifically SSI and PAA, when compared to direct appendectomy. Still the recommendation from our national guideline is to perform a direct appendectomy based upon good experiences in the pediatric academic centers.

In order to investigate the optimal treatment for children with complex appendicitis we will perform a nationwide, multi-center, comparative, prospective cohort study. For the purpose of this study, treatment strategies will be standardized among the participating hospitals in order to reduce heterogeneity. Prospectively derived, high quality data will be sufficient to answer the research questions regarding the optimal treatment strategy for each subtype of complex appendicitis in the pediatric population. As it is a non-randomized prospective cohort study, propensity score matching technique will be performed in order to estimate the effect of the treatments adjusted for potential confounders.

• Study Type: Observational
• Enrollment (Anticipated): 1308

Contacts and Locations

• Study Contact: Name: Ramon Gorter, MD PhD; Phone Number: 0031-205665693; Email: rr.gorter@amsterdamumc.nl
• Study Contact Backup: Name: Paul van Amstel, MD; Phone Number: 0031-205665693; Email: p.vanamstel@amsterdamumc.nl

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Recruiting
    • Northwest hospital group
    • Contact: Taco Bijlsma, MD PhD
  • Almere, Netherlands
    • Recruiting
    • Flevoziekenhuis
    • Contact: Gwen Diepenhorst, MD PhD
  • Amersfoort, Netherlands
    • Recruiting
    • Meander MC
    • Contact: Esther Consten, MD PhD
  • Amstelveen, Netherlands
    • Recruiting
    • Hospital Amstelland
    • Contact: Frank Garssen, MD PhD
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC - Location AMC
    • Contact: Ramon Gorter, MD PhD
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC - location VUmc
    • Contact: Ramon Gorter, MD PhD
  • Amsterdam, Netherlands
    • Recruiting
    • OLVG
    • Contact: Vanessa Leijdekkers, MD PhD
  • Apeldoorn, Netherlands
    • Recruiting
    • Gelre Hospital
    • Contact: Hugo Bolhuis, MD
  • Arnhem, Netherlands
    • Not yet recruiting
    • Rijnstate
    • Contact: Charlotte Blanken, MD PhD
  • Bergen Op Zoom, Netherlands
    • Recruiting
    • Bravis hospital
    • Contact: Floortje van Eijck, MD PhD
  • Beverwijk, Netherlands
    • Recruiting
    • Red Cross Hospital
    • Contact: Annebeth de Vries, MD PhD
  • Blaricum, Netherlands
    • Not yet recruiting
    • Tergooi
    • Contact: Nanette van Geloven, MD PhD
  • Breda, Netherlands
    • Recruiting
    • Amphia
    • Contact: Pieter Boele van Hensbroek, MD PhD
  • Capelle Aan Den IJssel, Netherlands
    • Recruiting
    • Ijsselland Hospital
    • Contact: Richard Groenendijk, MD PhD
  • Den Haag, Netherlands
    • Recruiting
    • Haga/JKZ
    • Contact: Gerda Zijp, MD PhD
  • Dordrecht, Netherlands
    • Recruiting
    • Albert Schweitzer Hospital
    • Contact: Maarten Lijkwan, MD PhD
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina hospital
    • Contact: Misha Luyer, MD PhD
  • Goes, Netherlands
    • Not yet recruiting
    • Admiraal de Ruyter Hospital
    • Contact: Jan Jansen, MD PhD
  • Groningen, Netherlands
    • Recruiting
    • UMCG
    • Contact: Jan Hulscher, MD PhD
  • Haarlem, Netherlands
    • Recruiting
    • Spaarne Gasthuis
    • Contact: Steven Oosterling, MD PhD
  • Heerlen, Netherlands
    • Recruiting
    • Zuyderland MC
    • Contact: Evert-Jan Boerma, MD PhD
  • Hoorn, Netherlands
    • Recruiting
    • Dijklander
    • Contact: Louise de Widt, MD PhD
  • Nieuwegein, Netherlands
    • Recruiting
    • Sint Antonius Hospital
    • Contact: Peter Go, MD PhD
  • Nijmegen, Netherlands
    • Recruiting
    • Radboud UMC
    • Contact: Ivo de Blaauw, MD PhD
  • Roermond, Netherlands
    • Recruiting
    • Laurentius
    • Contact: Jeroen Leijtens, MD PhD
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus MC
    • Contact: Claudia Keyzer, MD PhD
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Franciscus Gasthuis & Vlietland
    • Contact: Marijn Poelman, MD PhD
  • Rotterdam, Netherlands
    • Recruiting
    • Ikazia
    • Contact: Wouter Vles, MD PhD
  • Rotterdam, Netherlands
    • Recruiting
    • Maasstad Hospital
    • Contact: Charles van Rossem, MD PhD
  • Veldhoven, Netherlands
    • Recruiting
    • Maxima Medical Centre
    • Contact: Mart Bender, MD PhD
  • Zaandam, Netherlands
    • Not yet recruiting
    • Zaans Medical Centre
    • Contact: Frank den Boer, MD PhD
  • Zwolle, Netherlands
    • Recruiting
    • Isala
    • Contact: Vincent Nieuwenhuijs, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All children that present with a preoperative suspicion of complex appendicitis. This suspicion is based on 4 points or more on the abovementioned complex appendicitis scoring system OR a high index of suspicion of complex appendicitis by the treating physician.

Description

Inclusion Criteria:

Eligible for inclusion are all children <18 years old that need to undergo treatment for the suspicion of complex appendicitis. Suspicion of complex appendicitis is based upon the following predefined criteria:

4 or more points on our scoring system developed to predict complex appendicitis. The diagnostic accuracy of this scoring system is 91% (Range: 84-98%). This scoring system consists of five variables (clinical, biochemical and radiological,each awarded points). In case the total score is 4 or more points, the patient is likely to have complex appendicitis. Variables included in the scoring system are:

• Diffuse abdominal guarding (3 points)
• CRP level more than 38 mg/L (2 points)
• Signs on ultrasound / imaging indicative for complex appendicitis (2 points)
• More than one day abdominal pain (2 points)
• Temperature more than 37.5 degrees Celsius (1 point)

Or

High index of suspicion of complex appendicitis by the treating physician. If this is the case, the treating physician will make pre-treatment note upon what clinical, biochemical or radiological variable the high index of suspicion is based.

Exclusion Criteria:

• Adult patients (=18 years old)
• Children with a suspicion of simple appendicitis (based upon the previous mentioned scoring system and radiological features)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Complex appendicitis without abscess or mass formation; All children (<18 years old) that present with a suspicion of complex appendicitis without clinical or radiological signs of abscess or mass formation. Preoperative suspicion of complex appendicitis is based upon a previously developed clinical scoring system.	Procedure: Laparoscopic appendectomy; Laparoscopic appendectomy is performed according to daily practice but with the following standardized key points: Conventional laparoscopy (three-trocar technique); In case of purulent fluid: Suction and no peritoneal lavage procedure; Skelletizing of the mesoappendix (coagulation/clips according to routine practice locally); Appendiceal stump closure: with two endoloops and dissected between the endoloops. In case of involvement of the appendiceal base, the use of endostapler is recommended.; Withdrawal of appendix: principle of abdominal wall protection is followed (trocar technique / endobag); No drain placement, no nasogastric tube, and no urinary catheter routinely, only on indication.; Closure of wounds as appropriate; Procedure: Open appendectomy; Open appendectomy will be performed according to the following standardized key points: Gridiron incision at the right lower quadrant. (McBurney's point); After obtaining access to the abdominal cavity the principle of abdominal wall protection will be followed.; The appendiceal stump will be closed by ligation, not a purse string suture.; Closure of wounds as appropriate
Complex appendicitis with abscess or mass formation; All children (<18 years old) that present with a suspicion of complex appendicitis with clinical or radiological signs of abscess or mass formation. Preoperative suspicion of complex appendicitis is based upon a previously developed clinical scoring system.	Procedure: Non-operative treatment; Non-operative treatment consisting of administration of intravenous antibiotics with or without drainage procedures (in case of an abscess), reserving an appendectomy for those not responding or with recurrent disease. One of the two antibiotic regiments: Combination A:Amoxicillin/clavulanic acid 25/2.5mg/kg 6 hourly (total 100/10 mg/kg daily. Maximum 6000/600mg a day) for children <40 kg OR Amoxicillin/clavulanic acid 1000/200mg/kg 8 hourly (total 3000/6000 mg/kg daily) for children > 40 kgGentamicin 7mg/kg once daily; Combination B:Cefuroxim 25 mg/kg 6 hourly (total 100 mg/kg/day. Maximum 6gram/day)Metronidazole 10mg/kg 8hourly (total 30 mg/kg/day. Maximum 4000 mg/day) In case of peri-appendicular abscess the decision can be made to perform a drainage procedure either percutaneously or surgical.; Procedure: Direct appendectomy; laparoscopic or open appendectomy as described

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall complications	The proportion of patients experiencing any complication within 3 months after inclusion	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postappendectomy abscess	Proportion patients with a postappendectomy abscess	3 months
Superficial Site Infection	Proportion of patients with a superficial site infection	3 months
Secondary bowel obstruction	Proportion of patients with a secondary/prolonged bowel obstruction	3 months
Days absent from school, social or sports events	Number of days absent from school, social or sports events	30 days, 3 months
Number of days absent from work	Number of days that parents are absent from work	30 days, 3 months
Total number of extra visits	Total number of extra visits to the outpatient clinic, general pratctitioner's office or emergency department	30 days, 3 months
Length of hospital stay	Total length of hospital stay during follow-up due to trategy related treatment or complications	3 months
Level of pain	Level of pain measured according to the Visual Analogue Scale (0-10 points, higher scores indicating worse outcomes)	at inclusion/baseline (=day 0), 3 days, 5 days, 30 days, 3 months
Pain medication utilization	Pain medication utilization during admission	30 days, 3 months
Need for appendectomy	Proportion of patients not having to undergo appendectomy within 3 months after start of non-operative treatment	3 months
Recurrent appendicitis	Proportion of patients experiencing recurrent appendicitis within 3 months after inclusion	3 months
Early failure of non-operative treatment	Proportion of patients experiencing early failure of initial non-operative treatment	3 months
Quality of Life questionnaire (EQ-5d-Youth/EQ-5d-Proxy)	QoL measured by the validated EQ-5d-Youth / EQ-5d-Proxy questionnaire (0-1 point, higher scores indicating better outcome)	at inclusion/baseline (=day 0), 30 days, 3 months
Quality of Life questionnaire (PedsQL 4.0)	QoL measured by the validated Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) (0-100 points, higher scores indicating better outcome) Labor Questionnaire (HLQ), Medical Consumption Questionnaire (iMCQ) and Productivity Consumption Questionnaire (iPCQ) and gathered actual health care cost	at inclusion/baseline (=day 0), 30 days, 3 months
Medical costs (iMCQ)	Medical costs measured by the iMedical Consumption Questionnaire	at inclusion/baseline (=day 0), 30 days, 3 months
Non-medical / indirect costs (iPCQ)	Non-medical / indirect costs measured by the iProductivity Cost Questionnaire	at inclusion/baseline (=day 0), 30 days, 3 months
Quality adjusted life months (QALM's)	Quality adjusted life months calculated using outcomes 14 -17	3 months
Patient satisfaction questionnaire (PSQ-18)	Patient satisfaction measured by the Patient Satisfaction Questionnaire (PSQ) (0-100, higher scores indicating better outcome)	3 months
Patient satisfaction questionnaire (Net promotor score)	Patient satisfaction measured by the NET PROMOTOR SCORE (0-10, higher scores indicating better outcome)	3 months

Collaborators and Investigators

• Sponsor: Ramon Gorter
• Collaborators: Amsterdam UMC, location VUmc; ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Ramon Gorter, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• van Amstel P, Bakx R, van der Lee JH, van der Weide MC, Eekelen RV, Derikx JPM, van Heurn ELW, Gorter RR; CAPP collaborative study group. Identification of the optimal treatment strategy for complex appendicitis in the paediatric population: a protocol for a multicentre prospective cohort study (CAPP study). BMJ Open. 2022 Feb 17;12(2):e054826. doi: 10.1136/bmjopen-2021-054826.

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2019
• Primary Completion (Anticipated): May 12, 2023
• Study Completion (Anticipated): July 12, 2023

Study Registration Dates

• First Submitted: January 29, 2021
• First Submitted That Met QC Criteria: February 10, 2021
• First Posted (Actual): February 16, 2021

Study Record Updates

• Last Update Posted (Actual): July 25, 2022
• Last Update Submitted That Met QC Criteria: July 22, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Treatment; Children; Complex appendicitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Cecal Diseases; Intraabdominal Infections; Appendicitis
• Other Study ID Numbers: W18_302#18.348

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No