SGEM#345: Checking In, Checking Out for Non-Operative Treatment of Appendicitis

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Date: September 16th, 2021

Reference: Sippola et al. Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis. The APPAC II Randomized Clinical Trial. JAMA 2021

Guest Skeptic: Dr. Rob Leeper is an assistant professor of surgery at Western University and the London Health Sciences Center. His practice is in trauma, emergency general surgery, and critical care with an academic interest in ultrasound and medical simulation.

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Case: A 23-year-old man with CT confirmed uncomplicated appendicitis, mild abdominal pain, stable clinical signs, and essentially normal laboratory investigations has just concluded his bedside consultation with the on-call general surgery team. The patient and surgeons have had an evidence-informed discussion and have arrived at a mutually agreed upon decision to proceed with non-operative treatment of his appendicitis. The patient is recommended to undergo admission to hospital for serial observation and intravenous antibiotics. The patient asks; “gosh doc, if this disease is so mild why can’t I just go home and take antibiotics by mouth?”.

Dr. Eric Walser

Background: The appendix is a structure about as long as your pinkie finger that hangs off the beginning of the colon, in the right lower quadrant of your abdomen. There are lots of theories about subtle functions of the appendix, but its most prominent role is to become inflamed or infected in approximately 7% of people.

Usually appendicitis occurs because the lumen, or inside, of the appendix is obstructed by something. Often that is a piece of stool called a fecalith, but other times it can be lymph tissue or another process we may never actually identify. This causes the pressure in the appendix to increase eventually obstructing venous outflow and then arterial inflow.

We used to assume that this was an ordered progression that always leads to appendiceal rupture in a stepwise fashion, but we now think that there is more of a spectrum of severity based on individual anatomic and other factors. While the presentation of appendicitis can vary from patient to patient, as our emergency medicine colleagues know well, most patients are not diffusely peritonitic or systemically unwell.

Before we had things like surgery or antibiotics, appendicitis carried up to a 50% case fatality rate. Luckily now, with these treatments the mortality rate is almost zero. For the last 135 years we have treated appendicitis with an appendectomy, which is now almost always performed in laparoscopic fashion.

A laparoscopic appendectomy involves a general anesthetic, making three small incisions between 1 and 2 cm in length; and the operation usually takes somewhere between 30 to 60 minutes. Most patients go home the same day or the next morning, either with a short course of antibiotics or with none after surgery.

Most patients who have this surgery are back to work and their usual routine at around the two-week mark. The chance of requiring additional procedures is quite low unless we find that the appendix has already perforated. It is a good, and generally very safe operation, with a high rate of patient satisfaction.

Omar et al published a study in 2008 showing just how safe laparoscopic appendectomies have become. They found in over 230,000 UK patients the death rate was less than half compared to the open procedure (0.64% vs 0.29%; p<0.001).

Patrick Roy

Nonoperative treatment of appendicitis (NOTA) was first described in the 1940s and moved into the public consciousness when Patrick Roy was treated with antibiotics alone during the 1994 Stanley Cup playoffs. In 2014, tennis star Rafael Nadal was diagnosed with acute appendicitis. He was participating in the Shanghai Masters Tennis Tournament at the time. Nadal opted to be treated with antibiotics and had his appendix removed via laparoscopic one month later.

There have been several randomized trials like the APPAC trial and the CODA trial demonstrating that, in general, nonoperative management is safe, but that 25-60% of patients would go on to require an appendectomy during follow-up, which was usually around one year.

The recent Eastern Association for the Surgery of Trauma (EAST) guidelines from 2019 on appendicitis could not provide a recommendation on the use of NOTA as first line treatment. Despite this, we know from database studies that appendectomy remains far more common in North America, with nonoperative management reserved for remote areas or extenuating circumstances.

We have covered adult uncomplicated NOTA a couple of times on the SGEM. The first time was on SGEM#115 and we reviewed two SRMAs on the topic that came to opposite conclusions. The other time we looked at this issue was with Dr. Leeper on SGEM#256. We reviewed an observational study on NOTA.

SGEM Bottom Line: Nonoperative management of acute uncomplicated appendicitis may be better than we thought in selected patients but comes with a cost of a small absolute increase in some complications.

In that observational study by Sceats et al in JAMA 2019, all the patients were admitted to hospital for their antibiotic therapy or surgery. The study we are going to be looking at today compared outpatient vs. inpatient NOTA with antibiotics.

Clinical Question: Is a course of oral, outpatient antibiotic treatment non-inferior to a course of initial in-patient, IV antibiotics followed by completion of oral, outpatient antibiotics?

Population: Healthy adult patients aged 18 to 60 with CT proven, uncomplicated appendicitis without appendicolith. They defined uncomplicated as having an appendiceal diameter larger than 6 mm with a thickened, contrast-enhanced wall along with periappendiceal edema and/or minor fluid collection and the absence of the criteria of complicated acute appendicitis. Complicated was defined as the presence of appendicolith, perforation, abscess, or suspicion of tumor.
- Exclusions: They excluded those outside the age range, allergy to contrast media or iodine, allergy on contraindication to antibiotic therapy, kidney insufficiency or elevated serum creatinine level, type 2 diabetes, and use of metformin medication, severe systemic illness (eg, malignancy, medical condition requiring immunosuppressant medication), pregnancy or lactation.
Intervention: Oral antibiotics for seven days (moxifloxacin 400mg daily)
Comparison: Intravenous IV antibiotics for two days (ertapenem sodium 1 g once daily) followed by oral antibiotics for 5 days (levofloxacin 500 mg a day plus metronidazole 500 mg three times daily)
Outcome:
- Primary Outcome: Success at one-year. This was defined as resolution of acute appendicitis resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during the 1-year follow-up.
- Secondary Outcomes: Postintervention adverse events related to antibiotics or appendectomy, abdominal symptoms, duration of hospital stay, pain, and length of sick leave.

Authors’ Conclusions: “Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Yes
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were treated. No
The study patients were recruited consecutively (i.e. no selection bias). Yes
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. No
The treatment effect was large enough and precise enough to be clinically significant. Yes

Results: They randomized 599 patients, mean age was 36 years, and 44% were female.

Key Result: Outpatient oral antibiotics failed to show non-inferiority compared to inpatient IV antibiotics followed by outpatient oral antibiotics.

Primary Outcome: The treatment success rate at one year
- 70.2% outpatient oral vs 73.8% inpatient IV followed by outpatient oral
- −3.6% difference (1-sided 95% CI, −9.7% to ¥) p = 0.26
Secondary Outcomes: There were no statistical differences in any of the secondary outcomes measured.

1. Exclusions – They excluded pregnant and breastfeeding patients. This is a common exclusion and contributes to the lack of knowledge about how best to treat women (Women and Health Research IOM 1999). If there were concerns regarding lactation, potential participants could have been asked about bottle feeding temporarily during the study period.

2. Participation Rate – There were 1,036 patients eligible to be included in the trial. 433 declined to participate immediately (42%) and 16 more withdrew their consent after randomization. This means that 57% of patients agreed to NOTA. When using a script to explain the pros and cons of NOTA to patients, Minecci et al showed a real-life uptake of about 35% for NOTA in pediatric patients. What then was the discussion by the Finnish surgeons in the trial with patients about primary operative therapy? It reads as though this isn’t even offered anymore and that is both a) wrong and b) strongly colors my impression of the external validity of this trial.

3. Non-Inferiority Margin – This was set by the research team at 6% based on the APPAC trial. What would patients consider non-inferior? Perhaps now that we have a global pandemic patients would be more motivated to be treated as an outpatient and accept higher rate of failure if they could increase their chance of avoiding COVID. If the margin was set at 10% then they authors could have claimed non-inferiority.

4. Outcomes – It is hard to understand that there was no difference in hospital length of stay. It was 28.9 hours for outpatient management and 29.9 hours for inpatient management. How is this possible when one group had to stay for two days of IV antibiotic therapy and the other was supposedly sent home with oral antibiotics?

They also did not consider quality of life in their analysis. More than one-third of patients treated with NOTA would need to return to hospital within one year in both groups to have an appendectomy. They did not consider cost either. They asserts that analysis of the APPAC trial showed costs to be decreased NOTA but I wonder about the external validity of this result given database research done in North American centers.

5. External Validity – This multicentered trial was done in Finland. It is unsure how acceptable this approach would be to patients in other countries like Canada, USA, UK, rest of Europe and Australia.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: The claim of non-inferiority of outpatient oral antibiotics compared to inpatient IV antibiotics followed by outpatient oral antibiotics in healthy adult patients with NOTA is not supported with this data.

Case Resolution: The patient is told that outpatient, oral antibiotics alone has not been shown to be non-inferior to inpatient IV antibiotics. He decides to be admitted to hospital for his antibiotic treatment.

Dr. Rob Leeper

Clinical Application: This trial gives more clarity to the discussions that we all need to have with patients about treatment options, requirements, and expectations surrounding uncomplicated acute appendicitis. I’m still going to offer healthy young patients without appendicolith or signs of complicated appendicitis either an outpatient appendectomy (surgery and home four hours post op) versus admission for IV antibiotics and serial observations. In accordance with previously published literature, the majority still opt for an appendectomy.

What Do I Tell My Patient? I know you want to go home and just take pills. Unfortunately, evidence suggests this is not as good as being admitted to hospital on IV antibiotics. It will only be for 24-48 hours and them you can go home on pill antibiotics. He agrees to stay but wonders if he just should have had his appendix out and gotten this over with.

Keener Kontest: There was no winner again last week. The question was in what year and through what means was the first coronary angiogram performed? The answer was in 1958 within the Cleveland Clinic cardiology lab, when F. Mason Sones accidentally infused contrast into the right coronary artery, at the time assumed fatal, while performing a ventriculogram on a young man with rheumatic heart disease. The patient became asystolic, which resolved quickly after forceful coughing, and would prove the index case of coronary angiogram that cardiologists assumed would otherwise be lethal.

Listen to the SGEM podcast this week to hear the trivia question. If you think you know the answer, send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.