Episode 35 – Non Operative Treatment of Appendicitis (NOTA)

03 Apr
April 3, 2017

Background: Historically the treatment of uncomplicated appendicitis has been appendectomy. The first appendectomy performed dates back to 1735 done by Claudius Amyand. Appendectomy has been the standard treatment for acute appendicitis every since Charles McBurney described it in 1889. However, studies have shown that an antibiotic first strategy may be feasible without increased risk of perforation, sepsis, and/or death.  This other approach is called NOTA (Non-Operative Treatment of Appendicitis).  Past RCTs were from Europe and this is the first NIH grant study to question this in the US. Antibiotic first strategies are used for uncomplicated diverticulitis, but have not been used in uncomplicated appendicitis. Several reasons why this strategy may be preferred include fewer complications, less pain, and less disability than an appendectomy first strategy.  There have been a couple of systematic reviews on the issue of NOTA that came to different conclusions (Varadhan et al. BMJ 2012 and Kirby et al. J of Infection 2015). To date, no US randomized trial has evaluated an antibiotics-first approach in uncomplicated appendicitis until now.

Episode 35: Non Operative Treatment of Appendicitis

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Article:

  • Talan DA et al. Antibiotics-First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management. Ann Emerg Med 2016. S0196 – 0644(16): 30924 – 6. PMID: 27974169

Guest Skeptic Bio: Ken Milne is the Chief of Staff at South Huron Hospital Association in Exeter, Ontario, Canada. He is passionate about skepticism and critical thinking. He is the creator of the knowledge translation (KT) project, The Skeptics’ Guide to Emergency Medicine (www.TheSGEM.com). The SGEM tries to cut the KT window down from over 10 years to less than 1 year.

Lead Author Bio: Dr. David Talan was Chairman of the Olive View-UCLA Department of Emergency Medicine from 1993 to 2014. He is faculty of the Department of Emergency Medicine and Department of Medicine, Division of Infectious Diseases at Olive View-UCLA Medical Center. He is Professor of Medicine in Residence (Emeritus) at The David Geffen School of Medicine at UCLA. He is a Fellow of the American College of Emergency Physicians and the Infectious Diseases Society of America. Dr. Talan serves on the editorial boards of the Annals of Emergency Medicine, Emergency Medicine News, and Pediatric Emergency Care and is a reviewer for many journals including Clinical Infectious Diseases, JAMA, and The Medical Letter. 

Clinical Question: Is an antibiotics first strategy safe in patients with uncomplicated appendicitis?

PICO:

  • Population: Patients aged 5 years or older with uncomplicated appendicitis at 1 US hospital, observed in the emergency department for 6+ hours and then next day follow up (Diagnosis was by CT or Ultrasound)
    • Exclusions: Extensive (23 items in this list)
  • Intervention: Antibiotics First: Intravenous Ertapenem ≥48 hours followed by oral cefdinir and metronidazole in patients older than 13 years of age (i.e. Ertapenam dosing is BID in patients <13years of age)
  • Comparison: Appendectomy First
  • Outcome:
    • Primary: One month major complication rate
    • Secondary: Hospital duration, pain, disability, quality of life, hospital charges, and antibiotics-first appendectomy rate

Author’s Conclusions (from abstract): “A multicenter US trial comparing antibiotics-first to appendectomy, including outpatient management, is feasible to evaluate efficacy and safety.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the ED? Yes
  2. The patients were adequately randomized? Yes. A 1:1 treatment distribution was used
  3. The randomization process was concealed? Yes
  4. The patients were analyzed in the groups to which they were randomized? Yes. All patients completed therapy in their assigned groups
  5. The study patients were recruited consecutively (i.e. No selection bias.)? Unsure. They did include patients held overnight…”including those who presented overnight and were in the ED at 7am.”
  6. The patients in both groups were similar with respect to prognostic factors? Yes. Baseline characteristics were similar between treatment groups
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation? No. Patients clinicians, and outcome assessors could obviously tell who was treated with appendectomy first and antibiotics first.
  8. All groups were treated equally except for the intervention? Yes
  9. Follow-up was complete (i.e. at least 80% for both groups)? Yes. All except one patient was seen or contacted at each specified follow up visit
  10. All patient-important outcomes were considered? Yes. One month major complications rates.
  11. The treatment effect was large enough and precise enough to be clinically significant? No. As this is only a pilot study, a much larger study would be needed to confirm the results of this study

Key Results:

  • 30 patients consented:
    • 16 (53.3%) Antibiotics First
    • 14 (46.7%) Appendectomy First
    • Median age 33 years (Range: 9 – 73 years)
  • 14 of 15 Antibiotics first patients discharged from the ED with symptom resolution
  • 1 Month Complication Rates (Primary Outcome):
    • Antibiotics First 1/16 or 6.3% (95% CI 0.2 – 30.2%)
    • Appendectomy First 2/14 or 14.3% (95% CI 1.8 – 42.8%)
  • Total Hospital Time:
    • Antibiotics First 16.2hrs (Range: 10.9 – 106.6hrs)
    • Appendectomy First 42.1hrs (Range: 28.0 – 128.8hrs)
  • 12 Month Follow-Up:
    • 2 of 15 Antibiotics First patients (13.3%; 95% CI 3.7 – 37.9%) developed recurrent appendicitis

Strengths:

  • Assessed medication adherence to ensure compliance with antibiotics
  • Baseline characteristics were similar between treatment groups as well as qualifying patients not enrolled in the study
  • All participants had CT imaging with IV contrast, except 1 child, who had ultrasonography and 1 adult who had an elevated creatinine level
  • No crossover in study arms (Unlike other studies that had up to 53% crossover) 

Limitations:

  • A sample size of 30 patients was used for feasibility. This is 4.5% of what the projected sample size would need to be
  • Single center study
  • Investigators and patients were not blinded to management, but a sham surgery would be unethical
  • Complicated appendicitis can be missed preoperatively and commonly discovered at time of surgery, which was observed in 4 patients (28.6%)
  • 23 exclusions limiting the population this would apply too.
  • Over 1/3 (18/48 eligible patients) declined to participate. While appearing similar there may have been unmeasured confounders as to why they did not agree to be part of the study

Talking Nerdy with Lead Author David Talan:

Who was Excluded?

  • Inability to return or be contacted of follow-up visits
  • Evidence of severe sepsis or septic shock
  • High-risk diabetes (i.e. insulin dependent, diabetic ketoacidosis, hyperosmolar coma)
  • Immunodeficiency (i.e. absolute Neutrophil Count <500/uL, immunosuppressive drugs, chemotherapy, known AIDS [CD4 count <200uL or AIDS-defining illness within the last year]
  • Suspicion of acute coronary syndrome, congestive heart failure, or active chronic liver disease
  • Chronic renal insufficiency (Serum Cr >2 mg/dL)
  • Hepatic cirrhosis or failure
  • Acute inflammatory bowel disease or malignancy
  • Pregnant, nursing, or expectation of becoming pregnant within 10 days
  • Concurrent illness that would mandate hospitalization
  • Imaging findings suggesting a mass or mucocele
  • Severe allergy or reaction to study drugs or drugs similar to them
  • Receiving warfarin
  • Another infection requiring antibiotic treatment
  • Incarceration or police custody
  • Abdominal or pelvic surgery within the last month
  • Current long term care resident
  • Expected use of an investigational treatment
  • Intravenous drug use in the preceding month
  • Expected concurrent hemodialysis, peritoneal dialysis or indwelling peritoneal catheters or shunts, plasmapheresis, or hemoperfusion
  • Received parenteral antibiotics greater than or equal to 6 and less than or equal to 48 hours before screening
  • Received ertapenem within 24 hours before screening
  • Previous study enrollment

David Talan’s Thoughts: It is important to understand what we mean by complicated appendicitis (Complicated Appendicitis = ruptured appendicitis including perforation, phlegmon, or abscess). The purpose of the exclusions was to identify a group who did not have these characteristics. By the way the standard care for these patients not having signs of peritonitis, is not surgery, but antibiotics with or without a percutaneous drain. The most important exclusions included: immunocompromised state, comorbidities out of control (i.e. diabetic ketoacidosis), and evidence of severe sepsis and septic shock, but did not exclude patients with comorbidities such as diabetes mellitus with hyperglycemia.

What is the Number Needed to Treat?

  • ARR = 14.3% – 6.3% = 8%
  • NNT = 1/0.08 = 13
  • Due to the small number of patients however the 95% CI were very wide
  • Fragility Index is Zero. In other words, if one more person in the antibiotics first group had the primary outcome, then the results would be not statistically significant

David Talan’s Thoughts: This was a pilot study to test feasibility not to test the hypothesis of an antibiotic first strategy.  The primary outcome was development of major complications.  This outcome was used because it was independent of treatment strategy. Past studies have used the primary outcome of recurrent appendicitis, which makes sense because the major concern was without an operation there was the potential for failure of treatment or recurrent appendicitis in the future. There have now been 7 RCTs from Europe that have shown, that at least followed out to 1 year, an antibiotics first strategy is feasible with minimal recurrence.  Additionally, what patients care about falls into two general categories. The first category of patients fear that their appendix will burst and they could potentially die and the second group fears the surgery itself.  So if you are the type of patient that wants to avoid surgery, using an antibiotics first strategy could potentially result in an operation 25% of the time vs 100% of the time if you go forward with surgery. This study showed that for the patients fearful of surgery an antibiotics first strategy is a feasible option that would also avoid hospitalization.

Follow up was very robust:

  • Day 2 in person
  • Days 3 – 5 by telephone
  • 2 weeks (Days 10 – 18) in person
  • 1 Month (Days 25 – 35) in person

 David Talan’s Thoughts: This is the tension between a research study evaluating a non-standard treatment (i.e. patient safety and collecting data to inform the science) as opposed to a pragmatic trial which tries to understand how this would work in the real world. We have now started a larger multicenter study that is a more pragmatic design to fill in some of the follow up gaps.  We brought people back the next day, because no one had ever sent these patients home in the peer reviewed literature and patient safety was an obligation of our study. That being said, patients in this study were all substantially improved with the antibiotics first strategy. Going forward we may not have to have a next day follow up in person, but instead give very good discharge instructions and follow up with a phone call. Remember in the past we used to admit uncomplicated pyelonephritis and uncomplicated community acquired pneumonia and now we have learned if uncomplicated most patients could have treatment initiated in the ED and sent home with oral antibiotics.  We are now starting to learn the same thing with uncomplicated acute appendicitis.

 Antibiotics have known side effects?

  • Antibiotics First
    • 11/16 patients (69%) with Mild Diarrhea
    • 1/16 patients (6%) with Moderate Diarrhea
    • 7/16 patients (44%) with Mild Nausea
  • Appendectomy First
    • 1/14 Patients (7%) with Mild Diarrhea
    • 2/14 Patients (14%) with Mild Nausea

David Talan’s Thoughts: We also included major antibiotic related complications in this study (i.e. C. Diff Colitis, Other Types of  Colitis Leading to Hospital Admission, Stevens Johnson Syndrome, Anaphylaxis, etc). In this pilot study we didn’t have any cases of severe adverse antibiotic related complications.  What we did find, is patients exposed to more antibiotics (Oral antibiotics for 10 days vs only peri-operative antibiotics for 1 or 2days) had more minor complications such as nausea and diarrhea.

Appendicolith found on Computed tomographic

  • Antibiotics first = 2 (12.5%)
  • Appendectomy first = 3 (21.4%)
  • Appendicoliths have been associated with higher rate of antibiotic failure in some of the prior studies

David Talan’s Thoughts: This was an open design study, not a double blind study, therefore it allows physicians to bring their biases in regards to how they take care of patients. The finding of an appendicolith has been associated with complicated disease and we don’t really know why that is. But what is not known, is whether a patient that has an appendicolith without complicated disease is any more or less likely to respond to antibiotics in a non-operative treatment strategy. There is evidence that shows a higher likelihood to fail with  non-operative management of appendicitis in the presence of an appendicolith. But, what is not clear from these studies is if it was truly a failure, or the physician was not patient enough. So if you have the bias of appendicolith won’t be treated effectively with antibiotics and you have a patient on antibiotics who’s abdominal pain is not getting better in 24 hours or still having fevers at 24 hours you will be more likely to treat them with the operative route sooner instead of giving the antibiotics time to treat the disease. This is a sort of a self-fulfilling  prophecy so to speak. Interestingly, in this pilot study, of which 14 out of 15 patients were sent home with antibiotics, there were no antibiotic failures. This is different than previous studies that showed a 10% failure rate in patients being treated in the hospital. And this begs the question of did they actually fail therapy, or was the physician not patient enough.

David Talan’s Final Thoughts on Lessons Learned From This Paper:  A legitimate reason to say antibiotics have failed would be to say there are findings of peritonitis (this can be subjective), laboratory findings suggesting organ dysfunction/severe sepsis, and/or worsening after 48 hours of treatment. The second observation is that if a patient thinks they are going to cure their problem and their pain sooner, by getting their appendix out, they are wrong. Patients on antibiotics without surgery had relief of their symptoms 1 – 2 weeks sooner compared to patients with operative treatment. In addition, 1/3 of patients with acute appendicitis, treated with an antibiotics first strategy, were pain free and back to normal activities within 1 day of antibiotics.

Comment on author’s conclusion compared to REBEL Cast Conclusion: In this small pilot study, it seems reasonable to treat uncomplicated appendicitis as we would with uncomplicated diverticulitis.

REBEL Cast Bottom Line: Even though the results are very promising for using an antibiotic first strategy in acute uncomplicated appendicitis, a much larger trial would need to be performed before generalizability. Even so, this trial did show that outpatient ED management of uncomplicated appendicitis is feasible.

Other FOAMed Resources:

Post Peer Reviewed By: Matt Astin (Twitter: @mastinmd)

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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of R.E.B.E.L. EM

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  1. […] REBEL EM covered the issue of N.O.T.A. in adults when it reviewed a pilot study by Dr. David Talan (Ann Emerg Med 2016). Paediatric surgery is completely separate from adult surgery and the implications of practice in adults is not the same in children. There is not a lot of cross over for physicians who have both an adult and paediatric practice in the understanding that children are different. […]

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