Category: Surgery

The original APPAC was one of the first trials systematically testing an antibiotics-first strategy for appendicitis, demonstrating its feasibly and safety as an alternative to immediate surgery. Based on these and other data, reasonable differences of opinion exists regarding the favored approach. In Finland, however, where the original APPAC was performed, they’ve already moved on from the “if” question and onto “how best”.

In APPAC II, the “how best” question involves whether the initial treatment for uncomplicated appendicitis (no perforation, appendicolith, or tumor) need be intravenous, or whether a completely oral antibiotic strategy is noninferior. The intravenous strategy was comprised of two days of ertapenem, followed by five days of levofloxacin plus metronidazole, while the oral strategy was comprised of seven days of moxifloxacin monotherapy. All patients were hospitalized for observation for at least 20 hours, the minimum time necessary for two doses of intravenous antibiotics. The primary endpoint was treatment success at 1 year, defined as avoidance of surgery or recurrent appendicitis.

There were approximately 300 patients enrolled in each group, based on sample size estimates derived from their non-inferiority margin of -6% and an expected success rate of 73%. At one year follow-up, the success rate for the intravenous cohort was 73%, as compared with 70% for oral antibiotics. However, this did not meet their pre-defined margin for non-inferiority, as the difference of −3.6% had a one-sided 95% CI lower bound of -9.7%. This leads us into our favorite statistical wasteland, the land of not-non-inferior, yet also not inferior, nor equivalent.

These are interesting data, and, cutting through the statistical chicanery, it is most likely the outcomes in each arm are virtually indistinguishable. It is hard to tell, however, the advantage of adopting the oral strategy, as implemented, in the face of even a small amount of potential harm. Because all patients were hospitalized and observed inititally, the oral strategy does not avoid unnecessary bed utilization. It is not clear whether this initial hospitalization could be avoided; this initial timeframe constituted the greatest percentage of treatment failures, although this can also be potentially confounded by conservative clinical judgement and readily available operative resources.

The choice of moxifloxacin monotherapy as the comparator is interesting, as it is not strictly equivalent to levofloxacin plus metronidazole with respect to its anaerobic efficacy. It is rather baffling not to simply use levofloxacin plus metronidazole as the oral therapy in each group. The authors cite several publications demonstrating the viability of moxifloxacin monotherapy for intra-abdominal infections, but it seems to muddle the comparison unnecessarily.

In the end, these represent yet another interesting permutation in the approach to the non-surgical management of appendicitis. From a pragmatic standpoint, it seems rather mooted until such data exist showing patients can be managed without hospitalization. Then, if an acute emergency department evaluation is being performed, this provides plenty of opportunity to give at least a single intravenous dose of antibiotics, if warranted, rather than hewing dogmatically to oral-only – admitting fluoroquinolones have identical oral and intravenous bioavailability. These data raise as many follow-up questions as answers, unfortunately.

Finally, tucked into this publication is an even more interesting tidbit: APPAC III. Characterizing diverticulitis as “left-sided appendicitis”, and noting the relative inessential nature of antibiotics for diverticulitis, this currently-enrolling trial tests antibiotics versus placebo for uncomplicated appendicitis. In a world where others are slow to move beyond mandatory operative intervention, this group is testing zero intervention at all – fascinating!

“Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis”
https://jamanetwork.com/journals/jama/fullarticle/2775227

The classic, time-honored treatments for appendicitis are various forms of shamanism – swallowing lead balls, drinking pounds of quicksilver in hot water, or the application of slain young animals to the abdomen. The disease course of the classic patient, then, was obviously poor. In modern times, appendectomy. Ultra-modern, you might say, is antibiotics. Unfortunately, while the recurrence rate after appendectomy is quite low, short-term recurrence after antibiotics is disquietingly high – leading to additional questions regarding the durability of cure.

So, here are the 5-year outcomes of those patients initially entered into the APPAC randomized clinical trial. There were 530 patients randomized between 2009 and 2012 to either appendectomy or antibiotic therapy. Of the initial 257 randomized to antibiotics, 256 completed 1 year follow-up, 70 (27.3%) with recurrent appendicitis. Now, at 5 years, 246 were contacted for follow-up, with an additional 30 having undergone appendectomy. All told, this brings the total to a failure rate of 39.1% of antibiotic therapy in the original cohort. These authors also report quality-of-life and complication outcomes, but, as with the original trial, these are skewed because the initial cohort routinely underwent open appendectomy rather than laproscopic.

So, it seems as though the appendix, once identified as misbehaving, is prone to do it again. This does not disqualify antibiotics-first as a viable strategy for the treatment of uncomplicated acute appendicitis, but it would seem the long-term durability is more a coin flip rather than a roll of the dice.  That said, as long-term data grows more robust, it continues to push us in the direction of at least offering the option to our patients.

“Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2703354

Novelty is no guarantee of superiority. In the olden days, appendicitis meant: out, damned vestigial worm! In modern times, it gives rise to any number of potential antibiotics-first strategies, under observation or as an outpatient.

But, following resolution of the initial appendicitis symptoms, the appendix persists. And, left to its own devices, the risk of recurrence remains. In the few trials and observational series to date, the risk seems to be on the order of 20-30% at one year.

This study suggests the practical rate outside of controlled trial settings may be even higher. This retrospective review of administrative data from 45 pediatric hospitals examines management and resource utilization relating to appendicitis diagnoses. Over the six year study period, approximately 6% of cases of non-perforated appendicitis were managed non-operatively, a rate that increased 20% over the course of the study period – with most of the increase occurring in the final two years. Compared with those managed operatively, those managed non-operatively had higher rates of advanced imaging (8.9%), Emergency Department visits (11.2%), hospitalizations (43.7%) – and, finally, 46% of those managed non-operatively underwent subsequent appendectomy.

Interestingly, the median time elapsed before subsequent appendectomy was only one day – a result these authors found skewed relating to those who were discharged from the Emergency Department rather than after hospitalization for multiple doses of intravenous antibiotics. These authors also found 14% of those with recurrent appendicitis suffered perforation, a much higher proportion than the ~3% found in previous trials.

It certainly sounds appealing, from a superficial standpoint, to avoid surgery in anyone – least of all children. It is reasonable, however, to suggest the rush to transform practice to elevate non-operative management is unwarranted without better long-term data. Patients may be offered a non-operative management strategy, but only in the context of substantial uncertainty regarding ultimate outcomes, and the non-trivial risk of re-hospitalization for subsequent appendectomy.

“Outcomes of non-operative management of uncomplicated appendicitis”
http://pediatrics.aappublications.org/content/early/2017/05/31/peds.2017-0048

Antibiotics are unnecessary! No, antibiotics are great! No, we give too many antibiotics! It’s getting hard to keep track of which conditions we’re giving and withholding antibiotics for these days.

This article is a teaser for more evidence to come regarding strategies for managing appendicitis without surgical intervention. We’ve seen a few trials already, with essentially unconvincing results in either direction. A large trial regarding an antibiotics-first strategy in an adult population was criticized for using open surgical technique rather than laproscopic – and the one-year failure rate was still rather high. However, a pilot report in a pediatric population probably demonstrates an antibiotic-first strategy is still a reasonable option to present in shared decision-making.

This is a pilot project describing the initial results and feasibility outlook for an antibiotics-first protocol for appendicitis. In this protocol, patients randomized to an antibiotics-first strategy received an intravenous dose of ertapenem in the Emergency Department, were eligible for discharge directly from the Emergency Department, returned for a second dose of ertapenem the next day, and then completed an 8-day course of oral cefdinir and metronidazole.

In their pilot, 42 patients were screened and 30 patients consented for randomization. Of these, 15 were adults and 1 was a pediatric patient. Of the 15 adults, 14 felt well enough for discharge after initial Emergency Department observation. The pediatric protocol called for in-hospital observation regardless of symptoms at presentation.

The results are generally of lesser consequence than the effectiveness of this pilot demonstrating the feasibility of the protocol, and the yield at which patients could be enrolled for a larger trial. There were a couple instances of recurrent appendicitis in the antibiotics-first cohort, one of which was successfully treated with antibiotics a second time. There were a couple surgical complications in the surgery cohort. Costs and overall quality of life scores favored the antibiotics-only group, obviously – but, again, this sample is small enough none of these outcomes have been measured with reliable accuracy or precision.

I think it is reasonable to expect an antibiotics-first strategy to eventually take root as part of acceptable medical practice. However, I suspect this transition will be slow in coming – and more data would be quite helpful in determining any specific risks for antibiotic strategy failures.

“Antibiotics-First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management”

https://www.ncbi.nlm.nih.gov/pubmed/27974169

Effectively, that is the question raised by this study – regarding antibiotics vs. surgery for acute, uncomplicated appendicitis.

This is a pragmatic, prospective study conducted in the pediatrics population at Nationwide Children’s Hospital.  The intervention and comparison were simple: qualifying patients with objectively mild appendicitis were offered a choice between hospitalization and intravenous antibiotics alone, or appendectomy with 12 hours.

And, as generally expected, not every patient choosing antibiotics successfully completed follow-up without crossover.  Of the 37 patients and families choosing antibiotics, 2 failed initial hospitalization, another 2 failed within 30 days, and 5 more failed within a year.  Median follow-up was 21 months at the time of article submission, and no further patients had undergone appendectomy.  Of 65 children undergoing surgery, 5 had post-operative complications, two of which were major (re-hospitalization, re-operation).

However, as I stated above, the question raised regarding antibiotics and appendicitis – is it now necessary it be discussed?  Have we reached a critical mass in the literature where all patients with suspected uncomplicated disease be offered antibiotics-only?  It is certainly unreasonable foundation for a complaint if an informed consent for surgical treatment of appendicitis did not include an antibiotics-only strategy as a legitimate alternative.  It was, in this cohort, much less disabling, in general, and substantially cheaper.

If not now – the not-to-distant future.

“Effectiveness of Patient Choice in Nonoperative vs Surgical Management of Pediatric Uncomplicated Acute Appendicitis”
http://archsurg.jamanetwork.com/article.aspx?articleid=2475977