Category: Gastroenterology

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

New & Improved Glasgow Blatchford Score

Clinical decision instruments that predict short-term interventions and outcomes are fabulous things – precisely the sort of instruments that help Emergency Department physicians decide who will benefit from hospitalization.


This is the Glasgow Blatchford Score, a decision instrument applicable to presentations for upper gastrointestinal bleeding.  It has been “improved” by physicians from Kaiser, who have performed addition by subtraction – eliminating variables without a significant change in performance.  The original score has eight clinical features – the “improved” version has five, dropping chronic disease, melena, and syncope from the criteria.  Despite this, the AUC for therapeutic endpoints as well as for rebleeding and mortality is no different than the original score – at 0.85 and 0.83, respectively.


It is only a 200 patient cohort, and they don’t break down exactly how many patients were in each quartile of possible modified GBS, but essentially, a score of 0 or 1 means <5% chance of needing a clinical intervention, scores of 2-6 about 20% need an intervention, and anything above that is 70% chance of intervention.  The incremental improvement over regular physician judgement is not examined, but, more objective evidence is always better.


“A modified Glasgow Blatchford Score improves risk stratification in upper gastrointestinal bleed: a prospective comparison of scoring systems”

NICE Agrees – No PPI in UGIB

It’s hard to fight this battle in the United States.  It’s like hyperkalemia – where you carefully talk down the rotating IM intern from giving albuterol, terbutaline, bicarbonate, insulin, Kayexalate, and calcium to the K+ of 5.7 in your dialysis patient – and then the nephrology fellow on-call tells ’em to give it anyway.  Sigh.

But, in any event, despite the lack of evidence for benefit in patient-oriented outcomes for intravenous proton-pump inhibitors in UGIB, invariably the GI fellow wants it.  There’s even a suggestion of harms associated with IV PPIs in some of these studies – in addition to everything we’re learning about how gastric acidity contributes to the total body immune defense.  For all its criticisms, I think NICE – the clinical effectiveness consensus group in the United Kingdom – has gotten it right for UGIB.  Terlipressin, which isn’t available in the United States, appears to be beneficial in variceal bleeding.  Somatostatin analogues, not included in this guideline, may or may not be beneficial, and I agree that it was appropriate for them to be excluded.

In the meantime, I’ll keep fighting the inanity, one patient and one resident at a time….

“NICE clinical guideline 141 – Acute upper gastrointestinal bleeding: management”

Rational Clinical Examination: GI Bleeding

This series of articles, “The Rational Clinical Examination” in JAMA is by far one of my favorite approaches to medicine.  They ask simple clinical questions, and they do literature searches to find evidence to apply.  Additionally, the form in which they distill the evidence tends to be likelihood ratios – a far more useful statistical construct in estimating how a particular finding contributes to ruling-in or ruling-out disease.

This most recent literature review covers gastrointestinal bleeding – and it covers a few worthwhile points.  Most encouragingly, the authors are exceedingly skeptical about the utility of NG tube placement – reasonable positive LR for UGIB, but, as the authors note, a suspected source is usually well-established prior to NG tube placement.  Additionally, they note that the NG lavage does not tend to influence final patient-oriented outcomes – and lean towards not recommending its use.  Secondly, they also cover the Blatchford and Rockall scores, which are decision instruments that might have value in helping triage patients for outpatient management.

“Does This Patient Have a Severe Upper Gastrointestinal Bleed?”
www.ncbi.nlm.nih.gov/pubmed/22416103

Can We Stop Placing NG Tubes?

One of the worst-tolerated procedures in Emergency Medicine – placement of the NG tube.  Unfortunately, when I call my GI fellow on-call for any upper GI bleeding, the first question is invariably – what did the NG lavage show?

There is good evidence demonstrating that positive NG lavage tends to identify the presence of high-risk lesions found on subsequent endoscopy.  There is also evidence that endoscopic treatment of high-risk lesions decreases rebleeding and mortality.  So, if NG lavage identifies high-risk lesions, and endoscopic treatment of high-risk lesions decreases mortality, then patients who undergo NG lavage for their upper GI bleeds should have lower mortality, right?

This is a retrospective review of all the patients admitted to the West LA VA with a diagnosis of upper GI bleeding – a sample of 632 meeting inclusion criteria.  Of these, 255 did not undergo NGL and 378 did.  What’s interesting in this article is that the authors attempted to statistically create two identical cohorts using propensity scoring.  They ended up with two nearly identically matched cohorts of 193 patients from the original 632 based on demographics, triage, lab values, physiologic characteristics, and medical interventions.

Between these two groups, they found no significant difference between mortality, hospital stay, emergency surgery, and blood transfusion requirements.  There was a statistically significant difference in the number of patients who underwent endoscopy – patients who didn’t receive NGL had 60% endoscopy vs. 72.3% in the NGL group.  This is mildly interesting – considering that, in theory, the identification and endoscopic treatment of high-risk lesions is associated with increased survival – and if you’re doing less endoscopy on an identical patient cohort, you should be missing the opportunity to treat those lesions.  Yet, there was no significant difference outcomes between cohorts.

So, yes, if you wanted to stop placing NG tubes because they’re uncomfortable for patients and apparently don’t change ultimate outcomes – certainly, that may be reasonable.  Some gastroenterology literature suggests patient-specific risk factors are more important in predicting the impact of endoscopic intervention on outcomes, rather than the limited information derived from the NG lavage.

However, this is just statistical calisthenics in an attempt to replicated a randomized-controlled trial and doesn’t give us the prospective evidence needed to change practice.  Or argue over the phone with the GI fellow.

“Impact of nasogastric lavage on outcomes in acute GI bleeding”
http://www.ncbi.nlm.nih.gov/pubmed/21737077