Category: Surgery

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 ClinicalTrials.gov 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”
http://www.ncbi.nlm.nih.gov/pubmed/25728933

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.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860285/ (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)”
http://www.ncbi.nlm.nih.gov/pubmed/24646528

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”
http://www.nejm.org/doi/full/10.1056/NEJMoa1311367

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”
http://www.ncbi.nlm.nih.gov/pubmed/24379237

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”
http://pediatrics.aappublications.org/content/133/1/e39.abstract

Fewer CTs, More Ultrasounds in Children

It’s pretty clear that children shouldn’t be receiving CT scans, whenever possible.  Despite this, the rate of CT for the diagnosis of pediatric appendicitis continues to rise.


This is a retrospective review from the Medical University of South Carolina that describes their implementation of an imaging protocol designed to encourage ultrasound use.  They report before-and-after statistics for their protocol – and, unsurprisingly, they’re pro-ultrasound.


Their protocol is generally simple – if it’s clinical appendicitis, consult surgery.  If it’s uncertain, do ultrasound first – if ultrasound equivocal, do CT.  If the patient appears unwell, skip ultrasound and do CT to evaluate for perforation.  Their institution started out with 82% of patients undergoing appendectomy having received CT, with this percentage dropping to 20% following implementation of the protocol.  Their negative appendectomy rate was stable at 5% after implementation, as well.  They also note the cost of a pediatric CT is $6500 compared with ultrasound at $1100.


The main disadvantage of their protocol was the low sensitivity exhibited by ultrasound – 61% – and the length of stay resulting from patients who required both ultrasound and CT – nearly 8 hours.  Considering ultrasound sensitivity depends on the experience of the operator, efforts to implement this strategy might benefit from upgrading local ultrasound capabilities.


“Clinical Practice Guidelines for Pediatric Appendicitis Evaluation Can Decrease Computed Tomography Utilization While Maintaining Diagnostic Accuracy”
www.ncbi.nlm.nih.gov/pubmed/23611916‎

The Case of the Missing Appendix

The correct initial diagnostic imaging test to evaluate pediatric abdominal pain for appendicitis is an ultrasound.  It carries none of the risks associated with CT imaging – except for the increased risk of a non-diagnostic evaluation.  It is also highly operator dependent and suffers in centers without sufficient volume of abdominal ultrasonography.

This study evaluates the subset of ultrasonography reports with the dreaded result “Appendix not visualized.”  Overall, 37.7% of 662 consecutive ultrasonographic studies at the authors’ institution failed to visualize the appendix.  Of interest to these authors were the “secondary signs” of appendicitis – free fluid, pericecal inflammatory changes, prominent lymph nodes, and phlegmon.

Their results are quite complicated – and, woefully, not terribly helpful.  Free fluid in females – useless.  Free fluid in males – more helpful if there’s a lot, but still only 2 cases of appendicitis out of the 5 males with a moderate/large amount of free fluid.  Lymph nodes – useless.  Pericecal fat changes – 1 out of 4.  Phlegmon – 2 out of 2.

So, there’s some information here.  Secondary signs with “Appendix not visualized” are typically not diagnostic alone – but, depending on the summation of other clinical findings, may yet be enough to obviate supplemental CT.

“Appendix Not Seen: The Predictive Value of Secondary Inflammatory Sonographic Signs” 
www.ncbi.nlm.nih.gov/pubmed/23528502

Diverticulitis – The Sinusitis of the Colon?

Antibiotics are wonderful things.  They treat and provide life-saving amelioration of symptoms from the common cold, the flu, bronchitis, sinusitis, and otitis – or, more accurately, they don’t.  Rather than generalize the treatment with antibiotics for all these illness, it is rather the avoidance of antibiotics that should be generalized, with specific exceptions made as necessary.

The next “-itis” to go under the microscope is diverticulitis.  These authors from Iceland and Sweden deserve, at the minimum, kudos for innovation in swimming against the tide.  The treatment of acute diverticulitis – a febrile illness with an elevated WBC and left-lower quadrant pain – is generally gram-negative and anaerobic coverage as an inpatient or outpatient, depending on comorbidities.  These authors propose that diverticulitis is most frequently a self-limited process, rather than one that requires antibiotics.

This a non-blinded trial of antibiotics vs. non-treatment for CT-demonstrated acute, uncomplicated diverticulitis.  Over 600 patients were admitted, with half receiving simple observation and symptomatic treatment vs. half with the same plus antibiotics.  1% of patients in the antibiotic group suffered treatment failure – progression to abscess or perforation – compared with 2% of patients in the placebo group.

Unfortunately, we’re not quite done with antibiotics based on just this study.  It is unblinded with variable enrollment between centers, leading to several sources of potential bias.  Then, ten patients in the no-antibiotics group crossed over to receive antibiotics for clinical worsening during hospitalization.  However, this is still below the 6.5% complication rate the authors thought might be an acceptable failure rate for conservative therapy.

Many more questions to be answered regarding external validity, so hopefully this inspires other investigators to further explore which subset patients will derive benefit from antibiotics in diverticulitis.

“Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis”
www.ncbi.nlm.nih.gov/pubmed/22290281

Augmentin Is Non-Inferior to Appendectomy

A lovely study out of The Lancet that tells us what we already know…is not as right as we thought it was.  We’ve all seen the pediatric patient, usually female, that went to their pediatrician’s office with abdominal pain, had evidence of cystitis on a UA, and was prescribed amoxicillin or cephalexin.  They got a little better, but they’re still having some nausea, some pain, and some loose stools.  In your ED, the ultrasound is positive for free-fluid without visualization of the appendix, and a CT scan subsequently shows evidence for appendiceal rupture.  But – as we’ll see here – most cases probably resolved before you saw them.

This is a prospective study randomizing patients to antibiotics versus early surgery, and the antibiotic group here actually had a lot more success than we imagine – since all we see/remember are those patients where we discovered the “latent” appendicitis, partially treated and festering after that initial course of antibiotics.  Only 12% of their CT-proven uncomplicated appendicitis went on to have a appendectomy in the first 30 days, and 30% within a year.  So, you could almost argue that with an 88% short-term cure rate with antibiotics and a 70% medium-term cure rate, antibiotics should be first-line therapy with observation for clinical worsening.

Definitive therapy has its advantages – you could almost equate the appendix to the gallbladder, and say that the 30% recurrence is almost certain to rise in subsequent years.  But, is there an advantage to waiting to do an appendectomy on an elective basis?  Are the adhesions that might develop more or less of an issue that the risks associated with emergent surgery?  And, of course, in the female pelvis, any undertreated appendicitis represents a significant fertility risk.  This study raises great questions about whether we should change our practice regarding our approach to appendicitis, and it might just be we find a role for being less aggressive with surgery.

“Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial.”
http://www.ncbi.nlm.nih.gov/pubmed/21550483