No Pictures of Poop Needed

I like this article – not because of any specific quality improvement reason relating to their intervention, but because it reminded me of something of which I perform too many.

It’s an easy trap to fall into, the – “well, let’s just see how much poop is in there” for diagnostic reassurance and to help persuade the family you’re doing relevant testing in the Emergency Department. However, here are the relevant passages from their introduction:

In a 2014 clinical guideline, the North American and European Societies of Pediatric Gastroenterology, Hepatology, and Nutrition found that the evidence supports not performing an AXR to diagnose functional constipation.

and

Recent studies showed that AXRs performed in the ED for constipation resulted in increased return visits to the ED for the same problem.

I feel some solace in knowing that 50 to 70% of ED visits for constipation may include an abdominal radiograph as part of their workflow – meaning I’m just, at least, part of the herd.

So, regardless of the point of their article – that a plan-do-act cycle of education and provider feedback successfully cut their rate of radiography from 60% to 20% – this is yet another misleading and/or unnecessary test to delete from our practice routine.

“Reducing Unnecessary Imaging for Patients With Constipation in the Pediatric Emergency Department.”
https://www.ncbi.nlm.nih.gov/pubmed/28615355

Antibiotics for Diverticulitis, the End Must Be Near

I’ve talked about the inflammatory vs. infectious theory for diverticulitis in a couple of my national and international presentations, and I’ve talked about the evidence supporting an observation-only strategy. Until now, that evidence was mostly a single-center randomized trial from Finland, followed by an observational report from the same.

Now, this non-treatment paradigm has migrated across the little river between Scandanavia and Europe, and has been taken up by the Dutch in this latest randomized trial. In this trial, 22 clinical sites randomized 570 patients with uncomplicated diverticulitis to either admission for antibiotic treatment, or observation and disposition per clinical stability. The antibiotic chosen was amoxicillin-clavulanic acid, with ciprofloxacin/metronidazole in the case of allergy. The primary outcome was time to recovery, with secondary outcomes relating to complications and recurrence.

Of the 570 randomized, ultimately, only 528 were analyzed. A handful were lost to follow-up, and then 35 patients withdrew from the study after allocation – 22 in the observation cohort and 13 in the antibiotics cohort. There were minor, potentially confounding differences between the two cohorts analyzed – about 8% more of the antibiotics cohort suffered from mild or severe comorbid disease.

Most patients selected for observation were admitted – with only 13% managed as outpatients. With respect to the primary outcome, there was no difference between cohorts in time to recovery. There were also few statistically significant differences in secondary outcomes, although the numbers suggest a small magnitude of harm relating to observation. Complications – ongoing diverticulitis within 6 months, need for sigmoid resection, and hospital readmission – all favored the antibiotic cohort by small, non-significant amounts. Conversely, morbidity numbers generally favored the observation cohort – relating mostly to antibiotic-related adverse effects.

Regardless, the sum of benefits and harms – in the context of the other evidence – supports antibiotic-free strategies for uncomplicated diverticulitis.

“Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis”
http://onlinelibrary.wiley.com/doi/10.1002/bjs.10309/abstract

The Slow Demise of Antibiotics for Diverticulitis

We have been prescribing antibiotics for diverticulitis for an eternity.  Some patients, after all, do quite poorly without – and progress to perforation, sepsis, and death.  Very few clamor for such an outcome.  The question with diverticulitis has never been “antibiotics?”, only “inpatient or outpatient”?

Now, this dogmatic practice seems ripe to change.

This latest bit of published literature is an observational series from Sweden.  These authors followed up their previously-published randomized trial with an initial foray into practice change, considering the consistent harms of antibiotic overuse.  They prospectively enrolled 155 patients with CT-verified, uncomplicated diverticulitis and simply followed them after discharge without antibiotics.  Management consisted solely of pain control, typically paracetamol (acetaminophen), an initial liquid diet, and then gradual progression to full diet as tolerated.  Patients were followed daily by phone, at 1 week in clinic, and at 3 months again in clinic.

Of these 155 patients, there were a mere 4 treatment failures requiring admission.  This treatment failure rate is similar to the ~2.5% rate expected with antibiotics.  Two progressed to perforation and a third developed abscess – the last of which was apparent on re-review of the initial CT.  Each patient with progression was treated with antibiotics as an inpatient and recovered.

This is, however, an observational trial, and there were another 66 patients diagnosed with uncomplicated diverticulitis in the same time period but missed for enrollment.  This leads to concerns regarding selection bias, although the few presented clinical characteristics of the missed patients were similar to those included in the trial.  Patients were also excluded on the basis of many comorbidities thought to increase the risk of treatment failure, and those treated as inpatients.

But, at the least, in this trial and those prior, there is clearly a cohort of uncomplicated diverticulitis that derives little benefit from antibiotics.  And, furthermore, these few trials have not gone unnoticed: new guidelines in several countries, including the American Gastroenterological Association, have updates reflecting the validity of selective antibiotic use.

The evidence quality to date is still cumulatively low – but this is probably a treatment change paradigm just about ready for prime-time.

“Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: a prospective study”
http://www.ncbi.nlm.nih.gov/pubmed/25989930

“American Gastroenterological Association Institute Guideline on the Management of Acute Diverticulitis”
http://www.ncbi.nlm.nih.gov/pubmed/26453777

Just Poop, It Doesn’t Matter How

Hepatic encephalopathy, a consequence of bacterial overgrowth and impaired ammonia metabolism, contributes to (as these authors say) nearly $2B in healthcare costs due to hospitalization in the United States alone.  Typical, goal-oriented, modern therapy?  Lactulose, a non-digestible sugar, resulting in increased bowel movement frequency.

These authors, appropriately, challenge established dogma – noting, perhaps, there are more effective strategies for clearing the bowels.  As anyone who has undergone colonoscopy is aware, 4 liters of polyethylene glycol solution is the preferred – and highly-effective – bowel-cleansing method.  These authors, therefore, compare standard lactulose therapy with a forced high-volume intake of PEG solution.

With 50 patients randomized in generally similar distribution to either lactulose or PEG, the PEG solution group more rapidly cleared mentation within 24 hours – with 21 of 25 randomized to PEG making at least 1 point improvement on the hepatic encephalopathy scoring algorithm, compared with 13 of 25 in the lactulose cohort.  Victory!  Of course, this sample is too small to truly account for any adverse effects.  8 serious adverse events occurred, include 3 deaths, although the authors feel none were related to the differences between treatment strategies.  And, oddly, diarrhea was noted to be a more frequent adverse event in the PEG group.

Why is this odd?  Because increased frequency of bowel movements is critical to treatment success in HES – and, frankly, if they’re not seeing enough stool output in the lactulose group, they might be doing it wrong.  There’s no specific mention of outputs in the lactulose group, but, ideally, treatment of HES involves a rapid titration of lactulose to adequate stool volume, not a rigid treatment dose.  As such, I might suggest this is a bit of a straw-man comparator between PEG and lactulose, with regard to tests of superiority.

But, I applaud simply thinking outside the box.  Lactulose use has become somewhat dogmatic for the treatment of HES, when, clearly, the answer is just – poop, it doesn’t matter how.

Thanks to Rick Pescatore for forwarding this along.

“Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy”
http://www.ncbi.nlm.nih.gov/pubmed/25243839

Merry Christmas!

If you truly must read literature on Christmas, then I direct you to thebmj, and a selection of articles from its Christmas issue:

“Televised medical talk shows—what they recommend and the evidence to support their recommendations: a prospective observational study”
http://www.bmj.com/content/349/bmj.g7346

“CARTOONS KILL: casualties in animated recreational theater in an objective observational new study of kids’ introduction to loss of life”
http://www.bmj.com/content/349/bmj.g7184

“When somebody loses weight, where does the fat go?”
http://www.bmj.com/content/349/bmj.g7257

“Are some diets “mass murder”?”
http://www.bmj.com/content/349/bmj.g7654

Grilling Injuries on Memorial Day

If life were a generic action movie, otherwise idyllic backyard food preparation activity would be interrupted by nonsensical brawling.  And, invariably, the injuries occurring would probably include those suffered from direct contact – in effect, to grill the villainy out of the antagonist.

Reality is rather less sensationalist.  Indeed, apparently, the grilling injury of note is rather from the wire bristles on the grill cleaning implement.  These wire bristles become inadvertently detached, embedded in the culinary creations, and ultimately ingested.  As this CDC Morbidity and Mortality Weekly Report report on a small case series of grilling injuries states:

“The severity of injury ranged from puncture of the soft tissues of the neck, causing severe pain on swallowing, to perforation of the gastrointestinal tract requiring emergent surgery.”

Yet another hidden danger in the home!

“Injuries from ingestion of wire bristles from grill-cleaning brushes – Providence, Rhode Island, March 2011-June 2012.”
http://www.ncbi.nlm.nih.gov/pubmed/22763887

Nausea? We’ve Got Placebo For That

Turns out, there’s truth inside those late-night infomercials and flashing banner ads on the Internet:  the power to cure does, in fact, lie within ourselves.  Or, possibly at least, decrease nausea.

This is a randomized, blinded, placebo-controlled trial comparing 4mg IV ondansetron vs. 20mg IV metoclopramide vs. saline solution placebo in Emergency Department patients with nausea & vomiting.  258 patients were evaluated, mostly evenly distributed between groups, and with similar causes of nausea.  30 minutes after administration, similar decreases in nausea were noted in each group, best visualized in this graph:

There were no differences in patient satisfaction with therapy, but fewer patients in the metoclopramide group required rescue therapy, and a greater number of placebo patients failed to have any symptom improvement (non-significant).

What lesson can be drawn from this?  Uncertain.  It is probably fair to say there is some placebo effect at work, and, considering there are centrally-acting mechanisms for nausea, they may in fact be curative.  More likely, however, is that many of these causes of nausea & vomiting are simply self-limited, and resolve regardless of therapy.  Further research might evaluate which specific causes resolve without therapy, and thus reduce costs and adverse effects associated with anti-emetic therapy.

“Antiemetic Use for Nausea and Vomiting in Adult Emergency Department Patients: Randomized Controlled Trial Comparing Ondansetron, Metoclopramide, and Placebo”
http://www.ncbi.nlm.nih.gov/pubmed/24818542

4-Factor PCC, Skepticism and Surrogate Endpoints

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Despite a lack of clinical data supporting their superiority, 4-factor PCCs have been universally accepted as the intervention of choice for the reversal of Warfarin induced bleeding. While PCCs have demonstrated rapid normalization of INR values, they have yet to show any added value over FFP in true clinically relevant endpoints. In the largest RCT to date, 4-factor PCC corrected INR values far faster than FFP but with a mortality rate that was almost double that of the FFP group. In a recent small RCT published in American Journal of Emergency Medicine, Karaca et al attempted to demonstrate that 4-factor PCCs provide more than just surrogate benefits when treating Warfarin induced gastrointestinal hemorrhage.


In this small unblinded trial, 40 patients with clinically suspected upper GI bleeds were randomized to have their coagulopathy reversed by either FFP or Cofact, a 4-factor PCC. The outcomes examined by the authors were INR values at 2 and 6 hours, time-to-endoscopy, and percentage of patients with active hemorrhage at time of endoscopy (based on the Forrest Classification). Patients were required to have their INR level reach 2.1 before undergoing definitive endoscopic interventions. As is typical in FFP vs PCC trials, the dose of FFP used was bordering on a straw man dose at 10-15 cc/kg.

To what should be no one’s surprise, 4-factor PCC reduced INR levels significantly faster than FFP, and thus patients in the PCC group underwent endoscopy earlier than their FFP counterparts. Patients in the PCC group received their endoscopy on average at 8 hours after admission, while the FFP group underwent endoscopy closer to the 12 hour mark. Endoscopy revealed more patients with active hemorrhage (Forrest Classification 1a or 1b) in the FFP group (7 patients vs 0) and sclerotherapy was performed in 10 patients in the FFP group, with 1 in the PCC group. Furthermore 3 patients in the FFP group required further therapy due to rebleeding, while no events of rebleeding occurred in the PCC group.

These superiorities in surrogate and pseudo-surrogate endpoints did not translate into the patient oriented endpoint of mortality, which was equivalent (one patient in each group). As far as the dreaded complication of “thrombolic events” that has been associated with PCC use it is somewhat unclear. One patient in the PCC group experienced a fatal IVC thrombosis but authors claim this condition was a presenting malady rather than an adverse event due to the administration of PCC.

Once again PCC has found success upon examination of soft endpoints. In an unblinded trial with surrogate and subjective endpoints, it is unclear if the PCC group’s performance was due to the medication’s efficacy or simply random chance and a small cohort. Until superiority in concrete clinically relevant outcomes is demonstrated, we should be wary of the crown of supremacy PCCs currently flaunt.

“Use and effectiveness of PCC vs FFP in gastrointestinal hemorrhage due to warfarin usage in the emergency department”
www.ajemjournal.com/article/S0735-6757%2814%2900107-7/abstract

Direct Vascular Toxicity From PPIs

Proton-pump inhibitors have been the mainstay of many gastroesophageal disorders.  21 million people in the U.S. received a prescription for PPIs in 2009, associated with a cost of $13 billion globally.

Unsurprisingly, there are signals of harm from PPIs that are not completely understood.  It is recognized gastric pH is part of the body’s natural immune defense mechanism, and increased pH as a result of PPI use increases susceptibility to infection.  Additionally, some concerns have been documented regarding CPY2C19 inhibition, resulting in decreased clopidogrel activity.  However, multiple studies also point to increased vascular risk with PPIs that do not significantly inhibit CPY2C19.

These authors further explore the hypothesis the mechanism of PPI vascular risk has nothing to do with CPY2C19.  They find, through high-throughput chemical screening, that PPIs directly inhibit dimethylarginine dimethylaminohydrolase (DDAH).  This enzyme metabolizes asymmetrical dimethyarginine (ADMA), which is further responsible for inhibiting nitric oxide synthase (NOS).  In clinical terms, inhibition of NOS is a bad thing, and consistent with multiple clinical studies demonstrating increased ADMA activity is associated with cardiovascular death.

The in vivo portion of this study is limited by mouse model, but they do show a dose-dependent decrease in tissue nitric oxide associated with omeprazole administration.  The end clinical result of this would be increased oxidative stress, reduced vasodilator function, and otherwise impaired vasoprotective mechanisms.

It’s an interesting translational study uncovering a reasonable hypothesis for the recurrent themes of observed PPI harms.  It also tailors neatly into the prior clinical trial evidence suggesting PPI use in upper GI bleeding decreases bleeding-related deaths, while increasing non-bleeding deaths, resulting in no net mortality benefit.

The International Consensus and the American College of Gastroenterology guidelines say PPIs “may” be considered prior to endoscopy to downstage lesion severity, while NICE states PPIs should not be offered prior endoscopy for non-variceal UGIB.  The most recent Cochrane Review on the topic show no patient-oriented benefits to PPI prior to endoscopy.  I think it’s very reasonable to make an individualized decision whether the risks and costs associated with PPI use outweigh the benefits of acute clot stabilization in UGIB.

“Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”
www.ncbi.nlm.nih.gov/pubmed/23825361

Red Pill, Blue Pill, Video Pill

As these authors note, upper GI hemorrhage is responsible for almost 600,000 Emergency Department visits yearly – and there is some value and interest in risk-stratifying the suspect lesion with direct visualization.  Enter the gastroenterologist.

But, wait!  What if you could replace the on-call gastroenterologist and his endoscope with – a pill?  That was the question these researchers, funded by an unrestricted grant from the capsule endoscopy manufacturers, tried to address.

Sadly, their study design is woefully inadequate – except for producing positive findings to return the favor to their funding source.  A convenience sampling of 126 Emergency Physicians attending a conference watched four videos clipped only to footage of the stomach, three of which had blood present, and one of which did not.  These physicians missed a few (94% sensitivity) and overcalled a few more (87% specific) from these handpicked test videos.

So, we have a surrogate endpoint for patient-oriented outcomes, an idealized simulated setting that is non-equivalent to clinical practice, and conflicts of interest with the manufacturer.  The authors mention high “cost of capsule endoscopy” – and, at this point, I cannot see how this study does anything other than mislead readers this might be appropriate for an Emergency Department setting.

“Emergency Physicians Accurately Interpret Video Capsule Endoscopy Findings in Suspected Upper Gastrointestinal Hemorrhage: A Video Survey”
www.ncbi.nlm.nih.gov/pubmed/23859585