End Nail Dogma

In a world of doors, truck beds, furniture, and other finger-crushing nuisances, emergency department visits for injuries involving the distal digits are common. Injuries range from tuft fractures, to degloving injuries, to all manner of nail and nailbed derangement.

Perusing any textbook or online resource will typically advise some manner of repair, including, but not limited to, replacing an avulsed nail back into the proximal nail fold and securing it in place. If the avulsed nail is not available, recommendations include placing a bit of foil into the proximal nail fold. The general idea being that failure to do so will irretrievably scar the germinal matrix, resulting in some disfigured and mutant nail growth.

The NINJA trial tests whether this dogma is valid – and, rather unsurprisingly, finds it is not.

In this trial, children with finger nail and nailbed injuries requiring surgical repair were randomized, at the conclusion of the injury repair, either to replacement of the nail (or foil) into the nail fold, or to discard the nail and simply leave on a non-adherent dressing. The “c0-primary” outcomes were cosmetic appearance of the nail (using the Oxford Fingernail Appearance Score) and surgical-site infection at 1 week follow-up.

The majority of the 451 children involved were aged younger than 6 and most were crush injuries resulting in avulsion of the nail plate. The primary outcomes were no different between groups – 5 and 2 surgical-site infections in the “nail replacement” and “nail discarded” groups, respectively, and median OFNAS score was 5 (the highest score) in each group. Lest the trial be accused of just failing to demonstrate a difference favoring the “nail replacement” group, it was actually the “nail discarded” group having a non-significantly more favorable distribution of cosmetic scores.

When suggesting these results are unsurprising, it’s rather just a perspective many clinical encounters in the emergency department are “over-medicalized”, and receive unnecessary tests or treatment simply due to the spectrum bias associated with acute care. Most healthy human substrate is capable of healing from minor injury in a satisfactory fashion; hopefully, these results further inform the care of children with finger nail injuries, and, may be reasonably generalized to other nails and healthy adults.

Effectiveness of nail bed repair in children with or without replacing the fingernail: NINJA multicentre randomized clinical trial

APPAC II

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 Appendix Strikes Back

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

Yet More Love for the Alvarado Score?

The Alvarado Score for appendicitis has been around a long time – 1986, to be precise. Initially proposed to help with the diagnosis of appendicitis prior to advanced imaging, in a different surgical and observation culture, it has effectively been replaced in cost-effectiveness and timeliness by CT. These authors, however, want to resurrect it in the face of increasing CT overuse.

These authors perform a simple retrospective review of CTs performed at their single institution evaluating patients for abdominal pain, and then retrospectively calculated Alvarado scores from medical record review. Methods are incompletely described, but, effectively, they found about 20% of their 492 cases were Alvarado score ≥9 – and all had appendicitis – or Alvarado score ≤2 – and nearly all were absent appendicitis – and suggest any patients with scores at those extremes should not receive imaging, thus reducing ED length-of-stay and radiation exposure.

It should probably say something that a clinical tool has been around over 30 years without truly gaining traction. I don’t think their proposal is unreasonable – whether using Alvarado or gestalt – to consult prior to imaging for cases with high clinical likelihood, or to discharge with return instructions for cases that are inconsistent with the diagnosis. Cultural factors need to change on both ends of the spectrum, however, to support imaging reduction practice change. Finally, despite the commanding nature of their article title, this is hardly the level of evidence or statistical power to truly describe the safety or effectiveness of this strategy – there are more patients here than in many prospective studies, but this does not replace a well-designed trial, or even some sort of pre-/post-intervention report.

Also: “This study was presented at the 75th meeting of the American Association for the Surgery of Trauma, September 14-17th, 2016 in Waikoloa, Hawaii.” Ah, nice.

“The Alvarado Score Should Be Used To Reduce Emergency Department Length of Stay and Radiation Exposure in Select Patients with Abdominal Pain”

https://www.ncbi.nlm.nih.gov/pubmed/29521805

The Impermanence of Non-Operative Appendicitis Management

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

 

PCCs for Non-Warfarin ICH?

This quick post comes to you from the EMedHome weekly clinical pearl, which was forwarded along to me with a “Good stuff?” open-ended question.

The “good stuff” referred to a series of articles discussing the “CTA spot sign”, referring to a radiologic marker of ongoing extravasation of blood following an intracranial hemorrhage. As logically follows, ongoing bleeding into a closed space has been associated with relatively increased hematoma growth and poorer clinical outcomes.

However, the post also highlighted – more in an informational sense – an article highlighting potential use of prothrombin concentrate complexes for treatment of bleeding, regardless of anticoagulation status. We are all obviously familiar with their use in warfarin-related and factor Xa-associated ICH, but this article endeavors to promote a hypothesis for PCC use in the presence of any ICH with ongoing radiologically apparent bleeding.

The evidence produced to support their hypothesis? A retrospective 8 patient cohort of patients with ICH and CTA spot sign, half of whom received PCCs and half who did not. Given the obvious limitations regarding this level of evidence, along with problems of face validity, there is no reason to revisit their results. The EMedHome pearl seemed to suggest we ought to be aware of this therapy in case a specialist consultant requested it. Now, you are aware – expensive, unproven, and not indicated without a substantially greater level of evidence to support its use.

“Role of prothrombin complex concentrate (PCC) in Acute Intracerebral Hemorrhage with Positive CTA spot sign: An institutional experience at a regional and state designated stroke center”
https://www.ncbi.nlm.nih.gov/pubmed/27915393

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”

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

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”
http://archsurg.jamanetwork.com/article.aspx?articleid=2475977

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”
http://www.ncbi.nlm.nih.gov/pubmed/26091330

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”
http://jama.jamanetwork.com/article.aspx?articleid=2320315