Another Step in Antibiotics for Appendicitis

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”

The New “Standard of Care” for Appendicitis

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”

What Does EAST Say About ED Thoracotomy?

The resuscitative emergency thoracotomy in trauma – rarely used and rarely successful.  However, for appropriately selected patients in extremis, such timely intervention may be literally life-saving.

The downside: resource utilization associated with saving the neurologically unsalvageable and the risks to providers associated with the procedure.

This is an evidence synthesis performed by a group of authors affiliated with the Eastern Association for the Surgery of Trauma, addressing the topic of patient selection for Emergency Department thoracotomy.  Screening 2,152 studies to review, ultimately, 72, these authors review a total of 10,238 patient encounters in which patients underwent ED thoracotomy.  This results in six recommendations for patients presenting pulseless to the Emergency Department after trauma:

  • In patients with signs of life after penetrating thoracic injury: strongly recommend EDT.
  • In patients without signs of life after penetrating thoracic injury: conditionally recommend EDT.
  • In patients with signs of life after penetrating extra-thoracic injury: conditionally recommend EDT.
  • In patients without signs of life after penetrating extra-thoracic injury: conditionally recommend EDT.
  • In patients with signs of life after blunt injury: conditionally recommend EDT.
  • In patients without signs of life after blunt injury: conditionally recommend against EDT.

However, before you start rummaging around in your toolbox for the rib spreaders, it should be recognized the conditional recommendations – except in penetrating thoracic injury – result in absolute intact survival increases only in the range of 20-40 patients per 1000.  Therefore, unless you’re working in a setting of maximal effectiveness and experience, it is unlikely you’ll see even this small absolute benefit.  And, even in the setting with the strong recommendations and excess intact survival benefits of 100 patients per 1000 – your individual hospital system, based on institutional support and experience level of the providers involved, will need to develop specific policies for these situations.  Even though many ED physicians are capable of performing these heroic procedures based on their training, the remaining ED staff and systems in place may not be adequate to support the intervention.

“An evidence-based approach to patient selection for emergency department thoracotomy: A practice management guideline from the Eastern Association for the Surgery of Trauma”

The Era of the Appendectomy is Not Over

However, it might also be accurate to say: The Era of the Emergency Appendectomy is Over.

This is the Appendicitis Acuta trial, a multi-center trial from Finland, randomizing CT-diagnosed, suspected acute appendicitis to either antibiotics or immediate open appendectomy.  Randomizing 530 patents, the trial failed to meet its pre-specified endpoint of non-inferiority, as measured by the outcome of need for appendectomy within 1 year of the initial episode.

And, by “non-inferior”, I’m a little uncertain regarding their clinical interpretation of such.  Their statistical threshold, based on prior evidence, was a non-inferiority margin of 24%, and the actual rate of antibiotic treatment failure was 27%.  However, frankly, I’m not certain how even meeting their non-inferiority margin would be considered clinically acceptable.  I am all for innovating new, cost-effective approaches challenging classical dogma, but uncomplicated laproscopic appendectomies are just about the most-practiced, least harmful of surgical procedures.

The general argument in favor of antibiotics stems firstly from economic considerations – it’s far cheaper to use antibiotics – and secondly from avoidance of operative complications.  Even here, in which patients uncharacteristically underwent open appendectomies, the overall complication rate of 20.5% is inflated by 19 of 273 patients with superficial wound infections.  Minor, transient, treatable complications should not be included in such an analysis.  The 23 patients with continued pain and bowel symptoms at 1-year follow-up, however, is concerning.  But, again, whether such numbers from open appendectomies reflect the long-term symptom rate of laproscopic surgery is questionable.

This trial, at least, does seem to show an antibiotics-first strategy is not unreasonable.  Even as this was a negative trial, 72.7% of patients did avoid recurrent appendicitis and surgery – and of those who did require surgery, only a handful crossed-over on the initial hospitalization.  Additionally, the delay in definitive management was not specifically associated with increased complications.  It would be interesting to someday see 5- and 10-year follow-up, and whether further patients ultimately fail non-operative management, as truly, the lifetime recurrence rate is the better measure of a successful delayed antibiotic strategy.

I would not fault adoption of a strategy of offering antibiotics and observation – but, without better long-term data, I personally would be opting for the appendectomy.

“Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis”

FFP Vs. PCCs for Warfarin Reversal – Special Advertising Supplement

It is generally well-known, the advantages of Prothrombin Concentrate Complexes over Fresh Frozen Plasma.  They are a smaller-volume infusion, more rapidly reverse the anticoagulant effect, and lack some of other disadvantages of hemostatic product use.  This study, therefore, a Phase 3b open-label trial of PCCs vs. FFP for anticoagulation reversal before urgent surgery, is essentially of questionable utility.  Is it emergency surgery?  Then use the immediate reversal agent.  Is it semi-elective?  Well, why not wait a bit?

So, why even run a trial for the use of PCCs in the non-emergent realm?  Well, it rapidly becomes clear how this study was conceived by review of the “Role of the funding source”:

This research was funded by CSL Behring. A steering committee of academic medical experts and representatives of the funder oversaw the design and conduct of the study. The funder participated in the selection of the board members. The funder was responsible for data collection, management, and analysis of the data according to a predefined statistical analysis plan. Preparation and review of the Article and the decision to submit for publication was done by a publication steering committee that included academic medical experts and representatives of the funder. Medical writing assistance was paid for by the funder. JNG and RS had full access to all the data in the study and took responsibility for the integrity and accuracy of the data analysis.

The goal: “indication creep” – an entirely obvious corporate landgrab, essentially sponsored, conducted, and written by CSL Behring to expand the use of PCCs beyond emergency reversal.  Indeed, it’s hard to even dignify this Lancet content with a summary.  The exclusion criteria were extensive.  The trial was modified after a letter from the FDA.  Some of the reported outcome numbers in the paper don’t match their entry.  Almost all the differences in outcomes were subjective or surrogates for patient-oriented measures.  The authors conclusion:

“[T]hese data show that 4F-PCC is an effective and superior alternative to plasma in terms of haemostatic efficacy and rapid INR reduction for the rapid reversal of VKA therapy before urgent procedures.”

But, despite all these differences “favoring” PCCs, the surgical hemostasis was identical in practical terms – the difference in blood loss between cohorts was only 12 mL on average, only a handful of patients in each cohort required any sort of transfusion, and the total number of units transfused was nearly identical.  In fact, half of the FFP patients never had full INR reversal – with apparently no clinically important consequence.  Surgical cases went to the OR much faster with PCCs – so, as above, in an emergent or semi-emergent instance, PCCs are a great option.  Absent such a rush, however, ignore this Special Advertising Supplement masquerading as science in a supposedly reputable journal.

“Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial”

Independence Day History Lesson

July 4th, for our worldwide readers, is Independence Day in the United States.  This means the trauma centers fill up with all manner of traumatic and alcohol-related injuries.  Just as the Founding Fathers intended.

However, for your reading enjoyment today, I give you the medical biography of John Jones, the first Professor and Chair of Surgery in the American Colonies – as part of the group establishing the Columbia University College of Physician and Surgeons in 1767.

“John Jones, M.D.: pioneer, patriot, and founder of American surgery.” (free full text in PubMed Central)

The End of Appendectomies?

We’ve seen dogma challenged regarding diverticulitis and the necessity of antibiotics.  This isn’t the first post regarding a change in initial strategy for appendicitis, however, it’s certainly reasonable to revisit again as the evidence accumulates.

This study is simply a prospective, observational case series of 159 patients with acute, uncomplicated appendicitis.  In 2010, this institution in Italy made surgical appendectomy the exception, rather than the rule.  Patients without serious illness or complicated appendicitis were admitted for short term observation and started on amoxicillin-clavulanate.  Patients who failed to improve or worsened went to the OR.  Others were discharged and re-examined at 5-7 days as an outpatient, and, again, those without significant improvement went to the OR.  Over a 2 year follow-up period patients were assessed by phone.

Within 7 days, there were 19 (12%) treatment failures; 17 of 19 were acute appendicitis, 2 were tubo-ovarian abscess with secondary appendiceal inflammation.  Over the 2 year follow-up, 22 (13.8%) patients had recurrent appendicitis – 14 of which were managed with antibiotics without complication.  8 went to the OR, 6 of which were confirmed as acute appendicitis.

I don’t think we’d have the same issue with misdiagnosed TOAs in our population – 73% of their diagnoses were by ultrasound, and only 17% underwent CT.  12% short-term treatment failure is also nothing to scoff at – and this number is consistent with other studies.  Routine surgery, however, is much costlier, resource-intensive, and carries with it a similar or greater risk of major complications.  It seems to me this is absolutely a viable strategy.

Is it time surgery added “Consider a trial of antibiotic therapy prior to surgery for acute, uncomplicated appendicitis” to their Choosing Wisely list?

“The NOTA Study (Non Operative Treatment for Acute Appendicitis)”

Skull On, Skull Off, Disabled or Dead

What is a “good outcome” for stroke patients?  Is it “alive”?  Or is it “alive & independent”, as in most of the tPA trials?  Through what lens ought we interpret the findings of some of these highly intensive interventions for stroke?

This is DESTINY-II, which enrolled elderly patients with malignant intracranial swelling following significant MCA territory infarction.  In this study, patients were randomized either to usual care or hemicraniectomy, a potential life-saving intervention that relieves intracranial pressure and reduces cerebral herniation.  The untreated cohort had awful outcomes – at 12 months, zero patients were free from disability, zero had mild disability, and 5% had moderate disability.  The remainder were severely disabled in dead.  The hemicraniectomy cohort also had awful outcomes – at 12 months, zero patients were free from disability, zero had mild disability, and 6% had moderate disability.

So, of course, this study was stopped early because of overwhelming benefit to the hemicraniectomy cohort.

The key difference – hemicraniectomy patients survived to be severely disabled, while control patients died.  76% of patients in the control group died vs. 43% of the hemicraniectomy group.  Most of the difference was made up by patients with mRS 4: “Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance.“

Determining the value of survival with complete dependence vs. death is clearly a challenging ethical decision.  Should this therapy be more widespread, given the resource intensive care and the ultimately dismal disability outcomes?  Those questions remain to be answered – but at least this study helps us better share the prognosis of either option with patients and families.

“Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke”

Appendicitis Week Continues

As compared to the previously critiqued publication, I am rather pleased with the protocol described by these authors.

This is a clinical pathway for appendicitis from Children’s in Memphis prospectively evaluated for diagnostic accuracy.  They’ve taken the idealist route – risk-stratification, followed by discharge, ultrasound, or pediatric surgery evaluation.  These authors use the Pediatric Appendicitis Score, dropping patients into buckets based on scores 1-3, 4-7, and 8-10.  Most interestingly, there is no role for CT scanning in this pathway unless specifically requested by the consulting surgeon.

In this study, 196 children completed the full clinical pathway – 44 were in the low-risk group, 119 in the moderate-risk, and 33 in the high-risk group.  Almost all the low-risk patients were discharged from the Emergency Department with a telephone call follow-up, and only one patient had a callback – for what was eventually diagnosed as an omental infarct.  In the high-risk group, all 33 patients were admitted, and all 28 patients who were taken to the OR by surgery had appendicitis.  The 119 patients in the moderate-risk group are much more interesting.  33 of 119 ultimately had ultrasounds supporting a diagnosis of appendicitis, and all were confirmed in the OR.  However, the remainder of these patients either were discharged without ultrasound, or had negative ultrasounds.  There were, ultimately, 5 cases of appendicitis in the moderate-risk group, despite a negative ultrasound.

This is the main flaw in external validity of their protocol – what to do with a moderate-risk patient with a negative ultrasound?  Per the authors, the more concerning cases were admitted – either to surgery or pediatrics, depending on level of suspicion for an alternative diagnosis – or discharged with telephone follow-up.  I think many folks, when faced with this level of uncertainty, proceed to CT scan – but, amazingly, only 13 kids in this cohort were subjected to diagnostic or therapeutic radiation.  This statistic alone validates the protocol – and the cultural and operations changes necessary to make it work.  By having a safety net of follow-up calls in place for patients discharged from this clinical pathway, the pressure for an immediate diagnosis is eliminated.

It is a small sample size, and it requires providers to increase their comfort level with diagnostic uncertainty – but it certainly seems rational and promising.

“Prospective Evaluation of a Clinical Pathway for Suspected Appendicitis”

Zero-Miss or High-Yield for Appendicitis?

In a persistently befuddling contradiction, the same specialty that sometimes needs to be physically restrained from pan-CT-ing every trauma patient is simultaneously concerned about the negative appendectomy rate.  Maximum sensitivity in one instance, maximum specificity in the other.

An avenue that has been bludgeoned to death many a time is the utility of the WBC for diagnosis of appendicitis.  This study in Pediatrics out of U.C. Davis, again, attempts to establish test-thresholds for WBC to with the ultimate goal of reducing the negative appendectomy rate.  At U.C. Davis, similar to national rates, 2.6% of children taken for appendectomy were demonstrated to have a normal appendix.  They observe that neutrophil counts and overall WBC counts were within the normal range in over 80% of these patients, and describe a potential management strategy to improve their negative appendectomy rate.  For WBC <9,000 or <8,000, the negative appendectomy rate could be improved to 0.6% or 1.2% – as long as the surgeons were content with a sensitivity of 92% to 95%.

Thus the conundrum.  How many cases of appendicitis are you willing to allow to progress to perforation – associated with not-insignificant morbidity – in order to minimize the negative appendectomy rate?  Considering up to 20% of appendicitis will have a normal WBC count – despite addressing an important problem – the solution presented by these leukocytosis cut-offs does not appear to provide the ultimate answer.

“Use of White Blood Cell Count and Negative Appendectomy Rate”