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Reference:  St Peter, et al. Appendicectomy versus antibiotics for acute uncomplicated appendicitis in children: an open-label, international, multicentre, randomized noni-inferiority trial. The Lancet. Jan 2025

Date: March 19, 2025

Dr. Camille Wu

Guest Skeptic: Dr. Camille Wu is a paediatric surgeon based at Sydney Children’s Hospital where she is the Head of Department. She is also on the Training Committee of Paediatric Surgery for Australia and New Zealand.

Case: A 10-year-old boy presents to the emergency department (ED) with his parents. He started having abdominal pain yesterday and did not want to eat. Today, his abdominal pain worsened, and he developed a fever. On examination, he looks uncomfortable and is tender to palpation in the right lower quadrant. You tell the parents that his examination is concerning for appendicitis. You order an ultrasound that demonstrates a dilated and non-compressible appendix. You consult the surgery team and both of you come to speak with the family. His parents tell you, “His sister was diagnosed with appendicitis during the Covid pandemic. At that time, she was admitted to the hospital but just treated with antibiotics. She was able to go home and has done well since that time. Do you think he needs surgery, or can he be treated with antibiotics as well?”

Background: Acute appendicitis is one of the most common pediatric surgical complaints that we encounter in the ED. Traditionally, appendicectomy has been the gold standard for treatment, based on its effectiveness in preventing complications such as perforation, abscess formation, and peritonitis​. This is typically done laparoscopically through a few small incisions.

The concept of non-operative treatment of appendicitis (NOTA) with antibiotics has gained interest over the past decade. This has been supported by growing evidence suggesting that some cases of uncomplicated appendicitis may resolve without surgery​.

We have covered NOTA before on the SGEM that included some meta-analyses, randomized controlled trials, and observational studies.

  • SGEM #115: Complicated-Non-operative Treatment of Appendicitis (NOTA)
  • SGEM #180: The First Cut is the Deepest- N.O.T. for Paediatric Appendicitis
  • SGEM #256: Doctor Doctor Give Me the News, I Gotta Bad Case of RLQ Pain- Should I have an Appendectomy?
  • SGEM #345: Checking In, Checking Out for Non-Operative Treatment of Appendicitis (APPAC II RCT)
  • SGEM #384: Take Me Out Tonight, I Don’t Want to Perforate My Appendix Alright

The results have been mixed. Some of these studies have suggested that antibiotic therapy is non-inferior to surgical management while other studies have suggested antibiotic therapy did not meet criteria for non-inferiority compared to appendectomy. Most of these studies were conducted in the adult population with fewer studies conducted in children. The question remains:

To cut or not to cut?

Clinical Question: In children with acute uncomplicated appendicitis, is treatment with antibiotics non-inferior to appendicectomy?

Reference:  St Peter, et al. Appendicectomy versus antibiotics for acute uncomplicated appendicitis in children: an open-label, international, multicentre, randomized noni-inferiority trial. The Lancet. Jan 2025

  • Population: Children aged 5-16 years with suspected non-perforated appendicitis based on clinical diagnosis +/- imaging
    • Excluded: suspicion of perforated appendicitis, appendix mass/phlegmon, previous antibiotic treatment, positive pregnancy test, current treatment for malignancy, comorbid condition altering length of stay
  • Intervention: Antibiotic therapy, initially with IV antibiotics followed by oral antibiotics after clinical improvement
  • Comparison: Laparoscopic appendectomy
  • Outcome:
    • Primary Outcome: Treatment failure within 1 year.
    • Secondary: Complications (adverse events that required interventions without general anesthesia), length of hospital stay, patient-reported outcomes (quality of life and pain scores) and healthcare utilization.
  • Trial: Pragmatic, multicentre, parallel-group, unmasked, randomized, non-inferiority trial

Authors’ Conclusions: Based on cumulative failure rates and a 20% non-inferiority margin, antibiotic management of non-perforated appendicitis was inferior to appendicectomy.

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Unsure 
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes.
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No.
  8. All groups were treated equally except for the intervention. Unsure
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Unsure
  12. Financial conflicts of interest. None

Results: They recruited 936 patients from 11 children’s hospitals in Canada, the US, Finland, Sweden, and Singapore. 459 were assigned to the appendicectomy group and 477 were assigned to the antibiotic group.

Key Result: Antibiotic therapy was inferior to appendicectomy for management of non-perforated appendicitis.

Primary Outcome:

34% of the patients in the antibiotic group had treatment failure compared to 7% of the appendicectomy group. That was a difference of 26.7% (90%CI 22.4-30.9). Most treatment failure in the appendicectomy group was due to negative pathology.

In the antibiotic group, 72 (47%) met definition of treatment failure during the first admission.

Secondary Outcomes: 

Neither of the groups had deaths or serious adverse events.

The relative risk of having an adverse event related to the antibiotic treatment compared to the appendicectomy was 4.3 (95% CI 2.1-8.7). Most of these adverse events were classified as Gastrointestinal Distress.

Median length of stay was 1.0 day (IQR 0.76-1.68) for the appendicectomy group compared to 1.25 days (IQR 0.92-2.09) for the antibiotic group. The patients from the antibiotic group spent more time in the hospital during the 12 month follow up period 1.6 days (IQR 1.0-2.6) compared to 1.0 days (IQR 0.75-1.7).

The antibiotic group was able to return to normal activity and school faster than the appendicectomy group. They also did not require pain medications compared to the appendectomy Approximately three-quarters (73%) of the families surveyed from both groups reported being satisfied with their treatment.

Diagnosis of Appendicitis

In previous studies, the way a diagnosis of appendicitis is made has varied. Some studies have included imaging findings on CT scan or ultrasound. Some studies have included lab tests.

This study included patients with a diagnosis of simple, non-perforated appendicitis. They excluded those with suspicion of perforated appendicitis. How was this diagnosis made? We went back to the trial protocol on ClinicalTrials.gov to find some more details. It appears that all children with suspected acute non-perforated appendicitis were assessed by the on-call surgeon. The diagnosis could be made based on clinical suspicion with or without ultrasound imaging.

What is the gold standard for diagnosing appendicitis? We would imagine that surgical pathology consistent with the diagnosis is best but also recognize that is does not make any sense to remove the appendix of every child in the study.

Camille does not rely on imaging. However, often by the time she’s called to see the patient in ED, they’ve already had an ultrasound. Sometimes it’s helpful, sometimes it’s unnecessary, and sometimes it’s distracting. One of the common annoying scenarios is the finding of a mildly thickened 7mm appendix in a child who does have right inferior quadrant tenderness with no other signs of appendicitis, and parents are expecting an operation as the ultrasound says “appendicitis’ and the referring hospital has told them that’s why they were getting transferred. Many of these kids have a viral illness, causing lymphoid tissue in the wall of the appendix to hypertrophy, thereby enlarging the appendix.

Treat the patient, not the test or image finding.

Tests are an adjunct to clinical evaluation. They help us to confirm our diagnosis. How sure does a surgeon need to be to take a patient to theatre? How sure does an ED doctor need to be to call their surgeon to review? Seems like the threshold is different for different specialties, different hospitals, different practitioners, and different countries!

Selection Bias

Of the patients screened for eligibility in the study, 90% were excluded. Of those excluded, ~40% were excluded due to perforated appendicitis or suspected perforation, and the other 60% were excluded because they either declined to participate or “other reasons.”

Suspected perforation seems fairly subjective. I asked Camille to comment on how she clinically distinguishes between perforated or non-perforated appendicitis and the accuracy of making that determination based solely on physical exam.

  • Duration of symptoms: the authors also included duration ≥ or < 48 hours in their randomisation. Surgical teaching is that perforation occurs around Day 3, so be more suspicious of this group. Beware the kids under 5, they tend to perforate earlier at Day 2. Also be suspicious of pain on day 3 that’s suddenly better, but the patient is sicker.
  • Young and atypical presentation: presents like gastroenteritis, rather than the classic “central pain migrating to right inferior quadrant.” They don’t have a well-formed omentum, so are less able to cordon off their appendicitis. When the appendix starts to become gangrenous, the pus is not contained, and they get generalised peritonitis.
  • Pelvic appendicitis: the appendix tip is behind the bladder (or in front of the rectum). The inflammation in the tip is irritating the rectum. But also it means that the maximum point of tenderness is NOT in the right inferior quadrant but more central / pubic / pelvic. They may have abdominal dysuria or frequent urge to stool with not much evacuating.

The other group that was excluded were those who declined to participate or had other reasons. It would have been nice to know what those reasons were. A previous study found that a common reason parents declined to participate was they wanted to choose their treatment arm. Authors acknowledge this in the discussion section that they weren’t able to track the reasons for refusal or declined consents due to lack of funding.

Finally, another group that was excluded was pregnant patients, but pregnant people can get appendicitis too.

Appendicectomy Group vs. Antibiotic Group

There were two groups in this study, one group had surgery while the other received antibiotics. The patients in the antibiotic group received a minimum of 12 hours of IV antibiotics and were discharged if they were tolerating regular diet, pain was controlled, and vital signs were stable. If the patients in this group were not getting better, they could opt for another day of antibiotics or go for appendicectomy.  The surgical group was scheduled for appendicectomy in the next available slot. While these patients were waiting for the operating room, they also received IV antibiotics. The paper does not go into detail as to how long these patients who were in the surgery group waited. Previous research has demonstrated that it is fairly safe to delay surgery for appendicitis for 12 to 24 hours after presentation.

It is possible that these two group received similar treatment.  An antibiotic group  patient might have been on antibiotics for 1-2 days before changed over to getting an operation. An appendicectomy arm patient might be waiting 24-36 hours before getting their operation. Their study protocol specifies that the antibiotic group would have appendectomy by 48 hours if there was no clinical improvement. The surgery group would receive an appendectomy within 18 hours of randomization. We read both the paper and supplementary appendix to see if this actually occurred but couldn’t find any more information. And yes, a paper about appendicitis also has an appendix.

Additionally, the antibiotics given to patients may have varied. The authors write that the choice of antibiotic was dependent on the local centre. The variation in antibiotic regimen may also add some confounding but does help with generalizability. There is no consensus about the best antibiotic regimen for non-operative treatment of appendicitis.

Loss to Follow Up

The proportion of loss to follow up differed between the two groups. There was more data missing from the appendicectomy group compared to the antibiotic group (14% vs 5%). This may lead to attrition bias and over-estimate the treatment effect.

It is unclear why there was a higher proportion that were lost to follow up in the appendicectomy group. Is this because the patients who underwent appendicectomy did great and did not feel the need to follow up? Alternatively, did they not do as well? We don’t know.

Having more patients lost to follow up in the appendicectomy group may also lead to overestimating the difference in treatment failure between the two groups. The authors did perform a sensitivity analysis assuming event rates were the same in the missing data as the complete data without a change in their conclusions.

Non-inferiority Margin

The non-inferiority trial format is particularly relevant in this context, as it assesses whether antibiotic therapy is “not significantly worse” than surgery in terms of efficacy and safety.

This study had a proposed non-inferiority margin of 20%. This was decided as a compromise between patients and families and surgeons. Nonetheless, it is quite generous. Despite this margin that was set, this study still demonstrated that for appendicitis was inferior.

Different families and patients and surgeons probably have differing thresholds for how much risk of complications they are willing to tolerate.

The other question that we need to ask is what aspect of treatment is non-inferior? The primary outcome was treatment failure, but there were other aspects in the secondary outcomes that were also patient-oriented outcomes such as a faster return to school and activity, and less pain medication requirement in the antibiotic group. Those aspects may be more important to the family and patient. We saw very similar satisfaction rates between the two groups.

Although “appendicitis” is the one entity, it affects individuals in different ways, so that in patient-centered care, one size does not fit all.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion but think there is more research to be done to investigate if there is a subset of low-risk patients who may do well with non-operative treatment.

SGEM Bottom Line: When deciding between non-operative vs operative management of pediatric appendicitis, consider all three pillars of evidence-based medicine (the scientific literature, your clinical judgement, and the patient/family’s values and preferences).

Case Resolution: You and the surgical team engage in shared decision-making with the family and patient. You discuss the potential harms and benefits of operative versus non-operative management. The family expresses their desire to try and avoid surgery and the patient is admitted to the hospital for observation on IV antibiotics.

Clinical Application: 

Tune in to the podcast to hear how this paper changed or didn’t change Dr. Wu’s practice and her personal experience with non-operative treatment for appendicitis.

What do I tell my patient/family?

Thank you for your question. There have been many people studying whether we need to do surgery for appendicitis or if we can treat it with antibiotics. The results have been mixed. Let’s talk about the potential harms and benefits of each choice. If you decide that you want to try to avoid surgery, we can have your child stay in the hospital on IV antibiotics and observe him. If he gets better, we can send him home with oral antibiotics. If he gets worse or does not improve, we can revisit the discussion about performing surgery.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References

  1. The CODA Collaborative. A randomized trial comparing antibiotics with appendectomy for appendicitis. N Engl J Med. 2020;383(20):1907-1919.
  2. Jumah S, Wester T. Non-operative management of acute appendicitis in children. Pediatric Surgery International. 2022;39(1):11.
  3. Lipsett SC, Monuteaux MC, Shanahan KH, Bachur RG. Nonoperative management of uncomplicated appendicitis. Pediatrics. 2022;149(5):e2021054693.
  4. Decker E, Ndzi A, Kenny S, Harwood R. Systematic review and meta-analysis to compare the short- and long-term outcomes of non-operative management with early operative management of simple appendicitis in children after the covid-19 pandemic. Journal of Pediatric Surgery. 2024;59(6):1050-1057.
  5. Adams SE, Perera MRS, Fung S, Maxton J, Karpelowsky J. Non-operative management of uncomplicated appendicitis in children: a randomized, controlled, non-inferiority study evaluating safety and efficacy. ANZ J Surg. 2024;94(9):1569-1577.
  6. Kim SH, Park SJ, Park YY, Choi SI. Delayed appendectomy is safe in patients with acute nonperforated appendicitis. International Surgery. 2015;100(6):1004.
  7. Abou-Nukta F. Effects of delaying appendectomy for acute appendicitis for 12 to 24 hours. Arch Surg. 2006;141(5):504.
  8. Shin CS, Roh YN, Kim JI. Delayed appendectomy versus early appendectomy in the treatment of acute appendicitis: a retrospective study. World J Emerg Surg. 2014;9(1):8.

More SGEM Episodes on Appendicitis

  • SGEM#461: If You’re Appy and You Know It…Do You Need a Clinical Prediction Score?
  • SGEM#274: Hocus POCUS for Appendicitis?
  • SGEM#23: A Bump Up Ahead (Diagnosis of Appendicitis)