Thursday, February 16, 2012

STAT Treatment of Status

The lead article in today's New England Journal of Medicine is a randomized, double-blinded trial of IM midazolam (Versed) vs. IV lorazepam for the prehospital treatment of status epilepticus.  I don't know how many paramedics read this blog, but ER docs, hospitalists and neurologists will need to be familiar with RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial), so let's review it.

The study was designed to see if IM midazolam is noninferior to the current standard of care, IV lorazepam.  While lorazepam has been shown to be an effective initial treatment for status, it's not always easy to get IV access, especially while a patient is actively seizing.  Lorazepam also has to be refrigerated, unlike midazolam.

Adult or pediatric patients who had been continuously convulsing for 5 minutes, or those with intermittent seizures without regaining consciousness for 5 minutes, were eligible for the study.  Patients with certain acute precipitants of seizures, such as cardiac arrest, were excluded.  The paramedics tore open a study box, which activated a voice recorder.  The box contained an intramuscular auto-injector and a preloaded intravenous syringe.  One contained the active drug, while the other contained placebo.  The paramedics were instructed to give the IM medication first, then establish venous access and give the IV medication next.  During this time, EMS personnel verbally recorded when they gave the medication, and when the seizure stopped.

The primary outcome was the cessation of seizures before arrival to the ED, without the need for rescue medication.  Even though the study was powered for non-inferiority, IM midazolam ended up being superior to IV lorazepam: 73% in the midazolam group stopped seizing, compared to 63% of the lorazepam group.  The absolute risk reduction was 10%, with a respectable number needed to treat of 10.  There were no differences in the secondary outcomes of intubation or seizure recurrence.

RAMPART was randomized, double-blinded, intention-to-treat, with excellent follow-up (it's hard to lose an unconscious patient in an ambulance).  My only beef is that it seemed designed to give IM midazolam an edge:  the paramedics were instructed to give the IM drug before the IV one.  The trial could have randomized the order of medication given.  And indeed, the mean time to delivery of active treatment was significantly shorter in the IM group (1.2 minutes) than the IV group (4.8 minutes).  On the flip side, once the medication actually got into the patient, lorazepam was faster in terminating the seizure (1.6 minutes) than midazolam (3.3 minutes).

So is midazolam superior to lorazepam in the treatment of status, or is giving an IM medication just faster and thus superior to starting an IV?  We may never know.  The authors of this paper appropriately titled it "Intramuscular versus Intravenous Therapy..." instead of "Midazolam Is Superior to Lorazepam...."   Note that this study isn't applicable to patients who already have an IV.  If a hospital inpatient goes into status, it makes sense to give IV instead of IM treatment because of its faster onset.

Next post:  RAMPART was extremely well-designed.  But was it ethical?

Wednesday, February 15, 2012

Amoxicillin Effective for Sinusitis? It 'Snot.

How many studies does it take to prove a lack of clinical benefit?  There have been multiple randomized, controlled trials of antibiotics for acute, uncomplicated sinusitis, and meta-analyses have generally shown only a marginal benefit.  That's because the majority of sinusitis cases resolve spontaneously, given enough time.

So what's different about the latest RCT published in this issue of JAMA?  The authors of this study decided to test the CDC's conservative recommendations for antibiotic treatment, enrolling only patients who had moderate to severe symptoms present for at least a week.  (You could also be enrolled if your symptoms worsened within less than a week.)  Physicians diagnosed patients using clinical, rather than imaging, criteria, which closely mirrors what is done in the community.  Participants were randomized to either 10 days of amoxicillin or placebo.  A narrow-spectrum antibiotic was chosen, again in line with the CDC's recs, and at the time the study was performed, S. pneumoniae antibiotic resistance was rare.

The primary outcome was improvement in rhinosinusitis symptoms by day 3, as measured by the SNOT-16 scale.  (Hey, amoxicillin is a generic.  You're not going to find any sexy acronyms in this paper.)  The scale looked at 16 symptoms, rating them from 0 (none) to 3 (severe).  Both groups were allowed symptomatic treatment with pain relievers and decongestants.

One-hundred and sixty-six adults were enrolled.  The mean score on the SNOT-16 scale decreased from 1.7 to 1.1 in both groups by day 3.  There was also no difference in outcomes by day 10, with both groups dropping to 0.5.  There was a statistically significant decrease in symptoms in the amoxicillin group on day 7, but not a clinically significant one: the absolute difference in the symptom score was only 0.2.

Sinusitis accounts for 1 out of 5 antibiotic prescriptions in the U.S.  This well-designed trial confirms that they have but a borderline benefit, even in those with prolonged, moderate to severe symptoms.  Will primary care doctors finally listen to the results of this latest study?  

More importantly, will our patients?

Tuesday, February 14, 2012

Chocolate and the Happy Heart

In honor of Valentine's Day, one of our hospitalists, Tom Ormiston, gave a special "Bite-Sized EBM" presentation to the residents, covering a number of recent, thought-provoking papers.  One of them was a meta-analysis of chocolate consumption and the risk of cardiovascular and metabolic outcomes.  Before proceeding further, we must disclose a potential conflict of interest:  Dr. Ormiston passed out chocolate hearts to the audience (although no chocolate-sponsored ballpoint pens), and they were divine.

The meta-analysis included seven large observational studies of chocolate consumption.  The investigators chose to examine cardiometabolic outcomes, because of cocoa's purported "antioxidant, anti-hypertensive, anti-inflammatory, anti-atherogenic, and anti-thrombotic effects."  The analysis compared the participants who reported the highest level of chocolate consumption to those with the lowest. Here were there results:
Should this be called a Black Forest plot?

Remember, a relative risk (RR) less than one means that one group (in this case, the high chocolate group) has a lower rate of events than a comparison group (the low chocolate group).   The high chocolate group had an overall 37% decrease in the risk of cardiovascular disease, a 29% decrease in stroke, and no difference in heart failure.  Only one study, performed in Japan, looked at the risk of diabetes and found that there was a trend towards decreased diabetes in the high chocolate group.  The investigators had planned a subgroup analysis of dark vs. milk vs. white chocolate, but unfortunately, none of the studies collected this data.

All of you EBM acolytes can go ahead and start poking holes in this review:
  • All the studies were observational, and we know that when it comes to meta-analysis, garbage in,  garbage out.  In their defense, most of the studies were higher quality and controlled for confounders, such as body mass index, other dietary factors and education level.  Still, what about the intangibles -- are the lovelorn less likely to receive chocolate, and thus more likely to have a bad cardiovascular outcome?
  • The studies reported chocolate consumption using different scales.  "High" chocolate consumption could mean anything from at least once a week to more than once a day.
  • Some of the studies included only healthy participants, while others included those who already had a cardiovascular diagnosis.  Is chocolate useful only for primary prevention, or can it be used for secondary?
Before we become shills for Willy Wonka, let's recall the disappointing results of anti-oxidant vitamin trials, which held initial promise but may actually increase overall mortality.  And unlike typical dietary supplements, cocoa is usually consumed in high-fat, high-sugar form, so any recommendations for the consumption of chocolate would be premature.  The authors of this meta-analysis concluded appropriately, "Considering the limited data available, any conclusions should be cautious....Corroboration is now required from further test causation rather than just association."

But since it's Valentine's day, we don't wish to rain on anyone's parade.  Feel free to enjoy your chocolate, as long as you take it with a grain of sugar.