The Impact of a Diagnostic Strategy for Acute Appendicitis in Children with Acute Abdominal Pain in Primary Care

Not Applicable

Recruiting

• Conditions: Appendicitis Acute; Acute Abdomen in Children

• Registration Number: NCT06762275
• Lead Sponsor: University Medical Center Groningen

Brief Summary

BACKGROUND Acute appendicitis (AA) in an early stage is difficult to distinguish from other (self-limiting) causes of acute abdominal pain (e.g. constipation and gastroenteritis), resulting in missing 19% of children with AA at first presentation in primary care and 70% of non-AA cases among referrals.

OBJECTIVE To evaluate the impact of the use of a diagnostic strategy for acute appendicitis (AA), which consists of a clinical prediction rule (cPR) including C-reactive protein point-of-care test (CRP POCT), on referral efficiency in children with acute abdominal pain in primary care, as compared to usual care.

STUDY DESIGN This is a cluster randomized controlled trial in primary care with a process evaluation. GPs in the intervention group will use an externally validated cPR based on symptoms and signs selectively followed by a CRP POCT in the medium risk group. GPs from general practices allocated to the control group will provide care and diagnosis as usual, i.e. following recommendations of the Dutch College of GPs guideline 'abdominal pain in children'.

STUDY POPULATION Children aged 4 to 18 years presenting to their general practitioner (GP) with acute abdominal pain.

OUTCOME MEASURES Primary outcome: referral efficiency (proportion non-referrals in non-AA patients during 30 days follow-up).

Secondary outcomes: safety (proportion of referrals in AA patients during the first consultation), proportion of children with CRP-POCT, proportion of children with planned reassessment, child anxiety, parent or child satisfaction, quality of life, and costs.

Detailed Description

BACKGROUND About 10% of pediatric general practitioner (GP) consultations are for acute abdominal pain of which about 5% have acute appendicitis (AA). Delaying a diagnosis of AA and subsequent appendectomy increases the short and long-term morbidity. AA in an early stage is difficult to distinguish from other (self-limiting) causes of acute abdominal pain (e.g. urinary tract infection, constipation and gastroenteritis), resulting in missing 19% of children with AA at first presentation in primary care and 70% non-AA cases among referrals, which has a negative impact on the child and parents, such as anxiety and psychological distress.

As urgent illnesses other than AA are very rare in children with acute abdominal pain, the yield of referrals in terms of detecting other conditions than AA that need urgent specialist care is low. An evidence based diagnostic strategy for AA referral could help the GP in the diagnostic process, thereby reducing non-AA referrals without missing children with AA.

OBJECTIVE AND HYPOTHESIS The objective of this study is to evaluate the impact of a diagnostic strategy for AA, consisting of an externally validated cPR based on seven signs and symptoms, selectively followed by a CRP-POCT in the medium-risk group, on referral efficiency in children with acute abdominal pain in primary care, as compared with usual care. The hypothesis is that the diagnostic strategy will decrease the proportion of non-AA referrals, without delaying the diagnosis of AA.

STUDY DESIGN A pragmatic cluster RCT will be conducted with 1:1 permuted-block randomization of general practices to the intervention or control group using randomly varying block size. Stratification will be based on the GP practice size (greater or smaller than 5000 patients). Follow-up is 30 days for the primary outcome (efficiency) and 30 days and 3 months for secondary outcomes (7). Alongside the trial, a process evaluation will be performed according to the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance).

STUDY POPULATION Inclusion criteria are: children, 4 to 18 years, presenting with acute abdominal pain (onset ≤ 7 days) in primary care.

Exclusion criteria are: a history of appendectomy, pregnancy, traumatic cause of abdominal pain.

INTERVENTION The intervention in this study is a diagnostic strategy for AA referral using an externally validated cPR selectively followed by a CRP POCT in the medium risk group. By using the diagnostic strategy, GPs will evaluate a set of signs and symptoms on a structural basis and get guidance for indication and interpretation of CRP POCT, for which current practice is very heterogeneous. The cPR includes seven signs and symptoms of AA: sex (2 points), duration of symptoms (\< 24 hrs= 1 point, 24-48 hrs= 2 points), nausea or vomiting (2 points), elevated temperature (≥ 37.3 °C) (1 point), tenderness of the right lower quadrant (5 points), peritoneal irritation (4 points), and abnormal bowel sounds (1 point). For children in the low-risk group (score 0-7; mean probability AA 0.5%) safety netting advice should be provided. In the high-risk group (score ≥14; mean probability AA 41.0%), the GP should refer the patient to the emergency department. In the medium-risk group (score 8-13; mean probability AA 7.5%), GPs should perform CRP POCT according to Dutch laboratory quality standards. CRP values \<10mg/l (mean probability AA 1.3%) imply safety netting advice and for CRP \>50 mg/l a referral is needed (mean probability AA 41.8%). In case of a CRP value between 10 and 50 mg/l (mean probability AA 16.8%), the GP will discuss the following two management options with the patient: 1) a reconsultation later the same day or the next day; or 2) immediate referral. The cPR will be made available electronically for GPs, by a link integrated in the GP registry.

USUAL CARE Care provided as usual is according to the recommendations of the Dutch College of GPs guideline 'abdominal pain in children', which states that AA could be suspected when a child presents with pain and tenderness in the right lower quadrant and fever. Children with peritonitis signs and abnormal bowel sounds need to be referred. In case of doubt, GPs should perform safety netting and/or plan reassessment. CRP testing is not recommended, because lack of evidence for added diagnostic value in primary care. The GPs in the control group receive a leaflet with a summary of the NHG guideline 'abdominal pain in children'.

SAMPLE SIZE CALCULATION Results from previous studies show that the cut-off for the high-risk group based on the cPR had a specificity of 97% and that CRP value of ≥50 mg/l in children in the medium risk group had a specificity of 94%. As the weighted mean of these is a specificity (efficiency) of at least 95%, an improvement of efficiency from 88% (current care) to 95% is expected. In order to detect this difference, with 80% power, using a two-sided 5% significance level, and expecting 10% loss to follow-up, a randomized controlled trial would need to include 566 children (283 per group). The researchers assume to recruit on average 4 children per practice in 2 years and that 10 practices will not recruit any children. Therefore, 150 practices will be recruited which each recruit children for 2 years.

STATISTICAL ANALYSIS The primary outcome will be evaluated on an intention-to-treat basis. Children will be analyzed in the intervention or control group based on the GP practice in which they are registered, irrespective of the actual care received. In addition, a per protocol analysis will be done. In the intervention group according to the per protocol analysis, only children who received the intended diagnostic strategy and CRP-POCT testing in the prescribed way will be included. In the control group, we will only include children who did not undergo CRP POCT testing. Separately in both randomized groups, characteristics of children will be compared in the intention-to-treat and per-protocol analysis. A multilevel logistic regression model will be used to analyze the primary outcome, accounting for clustering of observations within GP practices and adjusting for the stratification variable (practice size) and, if necessary, for baseline differences. Exploratory analyses will assess subgroups by age and sex.

For secondary outcomes, multilevel logistic (dichotomous variables) or linear regression (continuous variables) will be used, as appropriate. In addition, adverse health outcomes (e.g. complications in AA cases and non-AA cases, missed other emergency diseases) will be described without statistical evaluation.

COST-EFFECTIVENESS ANALYSIS Cost-effectiveness will be calculated from societal and healthcare perspective with a time horizon of 30 days. Secondary analyses will address a 3-month time horizon. Efficiency will be the primary effect parameter. Cost-utility will be calculated based on the EQ-5D-(Y)-3L. Bootstrap re-sampling will be performed on the costs, and on costs and effect pairs (cost-effectiveness and cost-utility analyses) in order to calculate confidence intervals. Furthermore, both cost-effectiveness and cost-utility planes will be plotted, along with acceptability curves.

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-03
• Study First Submitted QC: 2024-12-31
• Study Start: 2025-03-06
• Study First Posted: 2025-03-25
• Last Update Submitted: 2025-03-25
• Last Update Posted: 2025-03-30
• Primary Completion: 2028-03-31
• Study Completion: 2029-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 566

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Referral efficiency	30 days follow-up from baseline	The referral efficiency is defined as the proportion of non-referrals in patients without AA during 30 days follow-up (development of appendicitis beyond this period is extremely unlikely). This corresponds with the specificity of the diagnostic strategy. Medical records of the participating children in the GPs registry, including discharge letters (hospital data), will be screened by the researchers, in order to assess whether children were referred and whether they were or were not diagnosed with AA.

Secondary Outcome Measures

Name	Time	Method
Proportion of children with planned reassessment	30 days follow-up from baseline	Proportion of children with planned reassessment in all children per randomized group. The researchers will use GP registry data to determine whether a reassessment was planned for each child. GPs will be explicitly instructed to document in the medical files whether a reassessment was planned or unplanned.
Safety	30 days follow-up from baseline	The safety is defined as the proportion of referrals in patients with AA during first consultation at the GP (baseline). This corresponds with the sensitivity of the diagnostic strategy. Medical records of the participating children in the GPs registry, including discharge letters (hospital data), will be screened by the researchers, in order to assess whether children were referred and whether they were or were not diagnosed with AA.
Proportion of children with CRP-POCT	30 days follow-up from baseline	Proportion of children with a CRP-POCT in primary care among all children per randomized group. The researchers will review data from the GP registry to identify whether a CRP-POCT was carried out for each child.
Anxiety of child ≥8 years according to the Dutch version of the State-Trait Anxiety Inventory for Children	30 days and 3 months follow-up from baseline	Children ≥8 years will complete the Dutch version of the State-Trait Anxiety Inventory for Children (STAIC) questionnaire. It measures self-perceived anxiety in children based on two scales: state-anxiety and trait-anxiety. The Dutch version of the STAIC (Zelfbeoordelingsvragenlijst voor Kinderen (ZBV-K) Versie Nu) questionnaire consists only of the state-anxiety scale. The questionnaire consists of 20 statements involving the current state of mind of the child. The score ranges from 20 to 60. The higher the score, the higher the level of state-anxiety of the child.
Parent or child satisfaction with management according to the Parental Medical Interview Scale (P-MISS)	30 days follow-up from baseline	Parents (for children 4-15 years) or children (16-18 years) will complete a Dutch translation of the P-MISS questionnaire. This questionnaire is used to measure the satisfaction of parents or children with the consultation at their GP for acute abdominal pain. The questionnaire consists of 26 statements about different aspects of the consultation. The child or parent has to rank each statement based on a Likert scale (1= do not agree at all, 5= totally agree). The maximum score is 130 and the minimum score is 26. The higher the score, the higher the satisfaction level.
Quality of life of child according to the EuroQol 5D (EQ-5D)	30 days and 3 months follow-up from baseline	For children ≤7 years, parents will complete the proxy version of the EQ-5D-3L. Children 8-14 years will complete the EQ-5D-youth and children ≥15 years will complete the EQ-5D questionnaire. The EQ-5D-3L is a standardized instrument which assesses the health-related quality of life of the child based on five domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (0), some problems (1), and extreme problems (2). The maximum score is 10 and the minimal score is 0. The EQ VAS records the parent- or self-rated current health of the child on a vertical analogue scale ranging from 0 ('Worst' to 100 ('Best').
Costs (societal and healthcare perspective)	30 days and 3 months follow-up from baseline	The costs for the effectiveness analysis and cost-utility analysis will be based upon an adapted version of the iMTA Productivity Costs Questionnaire (iPCQ) and iMTA Medical Consumption Questionnaire (iMCQ), through which data on health care consumption and productivity losses will be collected. Parents (for children ≤15 years) and/or children (≥16 years) will complete the adapted version of these questionnaires, which consists of a total of 16, respectively 18, questions about healthcare consumption, costs and productivity losses caused by abdominal complaints of the child. The units measured (medical consumption and productivity losses) will be monetarized according to guidelines of the National Healthcare Institute of the Netherlands. Thereafter, the costs of all items will be summed and weighted in conjunction with the outcomes in order to inform policymakers.

Trial Locations

Locations (1)

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands