Experimenting on the Unconscious

Those of you who read the last post about the RAMPART study, comparing IM midazolam to IV lorazepam in status epilepticus, may have wondered: How did the investigators obtain informed consent from the patients?  The answer is, they didn't.  At least, not until after the patient had already received the study medication.


There is no way to get prospective consent from an unconscious patient.  Even if a family member is present, time is of the essence when treating status.  The paramedics don't have the time to discuss the risks and benefits of the study, and families can't be expected to make a snap decision under duress.


This doesn't mean, though, that researchers are allowed to experiment willy-nilly on unconscious or confused patients.  The U.S. Food and Drug Administration allows exceptions to informed consent requirements under the following conditions (among others):

• Life-threatening condition requiring urgent intervention
• Unproven or unsatisfactory treatments
• Obtained informed consent is not feasible
• No reasonable way to prospectively identify individuals who may become eligible
• Possible direct benefit to study participants

Examples of patients who might be eligible for such a study include trauma or cardiac arrest victims.


Although the FDA tries to set clear criteria for what kinds of studies qualify for this exception, they leave room for interpretation.  For example, you can't really say that the standard treatment of status epilepticus is "unproven" or "unsatisfactory."  The majority of patients will respond to anticonvulsants, though some may require aggressive ICU support.  In addition, while a study may hold the promise of benefit to study participants, there is no guarantee against possible harm.


Perhaps the most notorious trial to meet the exemption from informed consent was the PolyHeme study, which randomized trauma patients to synthetic hemoglobin or crystalloid solution in the field.  While there was no overall difference in mortality, those in the PolyHeme group had significantly more adverse events, including myocardial infarction.


Even touchier, studies that qualify for the exemption from informed consent are bound to enroll more racial minorities, because of their higher rates of trauma or use of emergency medical services.  For example, one study found that blacks represented 41% of patients on a U.S. trauma registry, even though they comprised only 20% of the population in those areas. Moreover, the majority of trauma patients enrolled in a hypertonic saline trial, which waived prior informed consent, were black.  On a reassuring note, blacks who met the study eligibility criteria were not enrolled disproportionately more than other racial groups.  As for RAMPART, the authors noted in their results that "the overall number of subjects who were black reflected the proportion of blacks in the subject population from which the sample was drawn."  Whether this is enough to allay the suspicions of a community that has suffered from unethical experimentation in the past remains to be seen.


There is one way that patients can refuse to participate in such a trial.  In RAMPART, paramedics did not enroll patients who wore a medical-alert tag that read "RAMPART declined" -- but how would a patient know to wear such a tag in the first place?  The investigators are responsible for publicizing the trial, for example, in YouTube videos or newspaper ads.  Given that only about 400 patients have viewed RAMPART's video at the time of this posting, my guess is that most people, even those with seizure disorders, were unaware of the study or the fact that they could opt out.  It also seems unfair to place the burden on patients to wear these bracelets 24-7 just to avoid possible, unwanted experimentation.  And what if you want to avoid participating in all the emergency trials taking place in your area - must you don multiple tags or bracelets?

Despite these concerns, I still think RAMPART was an ethical study, and here's the reason why:  Even before the commencement of this trial, IM midazolam, the experimental treatment, was fast becoming the drug of choice among many EMS providers, due to its ease of storage and administration.  Surely performing a randomized trial of this drug in unconscious patients is more ethical than continuing to give those same patients a medication of uncertain efficacy.

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?

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