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Medically Clear: Distinguishing the ‘Mercury Cure’ from ‘Germ Theory’

Ballard, Dustin MD

doi: 10.1097/01.EEM.0000490524.84139.35
Medically Clear

Dr. Ballardis an emergency physician at San Rafael Kaiser, co-chair of the KP CREST (Clinical Research on Emergency Services and Treatments) Network, and the medical director for Marin County Emergency Medical Services. He is also the creator of the Medically Clear podcast on iTunes or athttps://medium.com/medically-clear. Follow him on Twitter at @dballard30.

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Long before there were patients who identified branded pharmaceuticals as superior to generics, there were those whose social class afforded them an opportunity for specialized medicine. High-class patrons living in the French Quarter of New Orleans in the early 19th century who suffered from port-city syphilis received gold-plated pills at our nation's first licensed pharmacy. The lower classes? Merely chocolate-coated pills. Having greater status in this case did equate to better health. Luckily for the rich, gold-plated pills passed through the GI system undigested, unwittingly conforming to “primum nil nocere.” The gold-encased pills protected patients from the mercury tucked inside, which was the standard treatment for syphilis at the time. Chocolate? Not so much. Thankfully, we no longer subscribe to the adage, “A night with Venus, a life with Mercury.”

Medicine was a shabby science in early 1800s America. Anyone, regardless of education, could start a practice. You needed no training to open a pharmacy and begin dispensing “cures” such as mercury, strychnine, and leeches. Pharmacists provided injections with lead needles and carefully avoided cleaning them between uses because a bloody and well-used needle was a sure sign of an experienced practitioner.

It was clear as I toured the New Orleans Pharmacy Museum in May that virtually every accepted “treatment” in the early 19th century was useless or harmful. We've come a long way since then. Our appreciation of germ theory and disapproval of dirty needles, for instance, is certainly an improvement. So is our understanding of effective drug delivery. Despite how far we've come, I think it's important for us to remember that medical science does not necessarily progress in a nice straight line. And picking through stacks of published research looking for a gem can be a perilous endeavor.

That brings me back to the New Orleans Pharmacy Museum and to the studies presented at the annual meeting of the Society for Academic Emergency Medicine that was held in New Orleans. Only a handful of the 670 abstracts presented will likely end up changing how we practice emergency medicine, and it will take some time to figure out which ones — to separate the mercury from the germ theory — but here is my early take on three studies that caught my attention.

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Icatibant for ACE-I Angioedema

Most people in 19th century New Orleans believed that diseases were caused by miasma, an affliction of “bad air.” One way city officials attempted to keep this noxious air at bay was with a show of force: They fired cannon balls into the swamp hourly and burned tar along the perimeter of the French Quarter to create protective smoke. Citizens of the day were convinced that such interventions were effective and that burning tar was unrelated to miasma. The smoke discouraged mosquito swarming and malaria transmission, but, of course, also contributed to rampant respiratory illnesses. Fast forward to present day. Don't we still encounter treatments that at first may seem to work but on consideration don't pass muster? Research presented at SAEM shot a cannon at one such promising treatment.

Angioedema secondary to ACE-inhibitor (ACE-I) treatment is a relatively new affliction in the annals of disease and one that, while relatively uncommon (affecting less than 1% of those taking the drugs), has limited treatment options. A small phase II trial (the 27-subject AMACE study) suggested treatment with icatibant at 30 mg subcutaneous. Given concomitantly with an antihistamine and a glucocorticoid showed a significant shortening of time to edema resolution compared with standard therapy.

A study presented at SAEM, however, by Richard Sinert, DO, (SUNY Downstate Medical Center) and colleagues shed some noxious miasma on the enthusiasm. The study was a phase III randomized double-blind trial of icatibant 30 mg SQ vs. placebo SQ in adults presenting to the ED with at least moderately severe angioedema of less than 12 hours' duration. The investigators enrolled 121 patients across 31 sites.

The patients were similar across demographic, time-of-onset, and supplemental treatment (antihistamine, steroids, epinephrine) characteristics. The icatibant group demonstrated higher rates of minor adverse reactions such as injection site inflammation, but unfortunately no difference in the primary end-point, defined a priori as the “time to meeting discharge criteria” (TMDC) after drug administration. The TMDC, a four-component clinical score assessment based on breathing, swallowing, tongue, and voice change criteria was four hours in both groups.

“At present,” Dr. Sinert concluded, “I do not think there is a suitable agent to treat ACE-I angioedema other than supportive care and waiting for the ACE-I to wear off.”

On the other hand, with so few viable options in our therapeutic armamentarium for ACE-I angioedema, it may be that icatibant could be a relatively harmless adjunct to consider for cases of severe angioedema.

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Implicit Bias in Evaluations

Our current emphasis on disparities makes us well aware of how the nature and quality of medical care can differ based on race, ethnicity, and gender. It was no different two centuries ago. In fact, disparities were far more ghastly. Eighteenth-century women would salve themselves with strychnine paste to achieve the skin hue considered beautiful in those times — a pasty and cyanotic teal caused by progressive hypoxia from diaphragmatic paralysis. Women were allowed to practice such questionable aesthetic techniques, but they were not allowed to practice medicine in the 19th century.

We have come a long way in this regard, but some long-held implicit biases are still at play. Consider the SAEM plenary presentation by Arjun Dayal and Daniel M. O'Conner (medical students at the University of Chicago) and Vineet Arora (University of Pennsylvania) entitled “Going the Extra Mile: Predictors of Higher Milestone Achievement in Emergency Medicine Using Longitudinal Multicenter Direct Observation Data.”

This study compared 34,758 directly observed resident evaluations collected between 2013 and 2015 across 359 residents and eight EDs based on gender (resident and faculty) and experience. The observations were recorded in an app called InstantEval (http://instanteval.com/) that provides evaluators with an opportunity to record real-time feedback on resident performance and, in particular, ACGME-defined “milestone” acquisition over time across 23 subcompetencies. The milestone subcompetencies cover skills and knowledge, and include airway management, patient-centered communication, and pharmacotherapy. The study utilized a mixed effects ordinal regression model and, not surprisingly, found that ratings of milestone acquisition were strongly and positively related to resident experience levels. They also found that the gender of the evaluator and the gender pairing of the evaluator/evaluee did not have a significant effect on milestone ranking. These findings got little attention at SAEM, but the additional finding of consistently higher rankings for male residents than female residents, starting in the second year of residency, (p<0.001) definitely did.

Several audience comments, including one from Stacey Poznanski, DO, the outgoing president of the Academy for Women in Academic Emergency Medicine, praised the study for being gutsy enough to ask the difficult (and loaded) question of whether implicit gender bias exists in resident evaluations.

Another audience member asked if it were possible that the evaluation pattern captured a true trend — that experienced male residents truly performed better than female. The authors thought this was unlikely for a host of reasons that are summarized in a follow-up written statement by doctor-to-be O'Conner:

“We think it's likely that the gender differences in our study are at least partially driven by systemic, implicit bias. We found that men and women were evaluated similarly at the beginning of training, suggesting that male and female residents entered training with similar skills and knowledge. However, as women progressed through the same residency programs, they were consistently evaluated lower than their male colleagues. Though disparities related to opportunities or mentoring may have been contributing factors, the relatively equal number of evaluations given to male and female residents suggests that both received similar amounts of direct-observation feedback. By PGY3, women were evaluated lower on all 23 EM subcompetencies. Such a uniform trend, with comparable evaluations at the beginning of residency, strongly implicates bias rather than diminished competency or skill.”

The investigators have a manuscript under preparation, and we will see how the methods and findings hold up to peer-review scrutiny. If they do, we can expect an interesting debate about how to correct for implicit bias in our residency programs, a debate that hopefully will be less toxic than strychnine body paste.

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Opioid Prescribing

A favorite type of therapy at America's first licensed pharmacy was an ancient one, derived from poppy seeds. Laudanum — opium mixed with alcohol — was a popular treatment for a common affliction known in those days as the woes. Given its potent recipe, it's no wonder that it helped alleviate the discomforts of acute or chronic disease and that “hysteria” ensued when patients ran out of it. Patients who wanted something newfangled could also try heroin, concocted in the 1800s by the good people at Bayer.

We can blame 19th century pharmacists for helping to create opioid addicts, but we can't deny that we still struggle to control the seed of the poppy. Emergency physicians have been identified as enablers of addiction and, in some cases, as the source. Perhaps, though, there is some good news from SAEM regarding efforts to educate EPs in best practices for opioid prescriptions.

Scott G. Weiner, MD, MPH (Brigham and Women's Hospital), and colleagues queried the state of Ohio's Prescription Drug Management Program to study the patterns of ED opioid prescriptions between 2010 and 2014. They found 2,791,632 prescriptions for opioids by 1,855 EPs in Ohio (averaging 301 prescriptions per physician per year), which reminds me of the maxim, “A Norco prescription a day will keep the drug-seeker in the ED waiting bay.” Fortunately, though, numbers of prescriptions steadily declined each year, and the 2014 total was almost half that of 2010. As in the 1800s, more women received opiates from their doctors than men (57% vs. 43% of all prescriptions), but unlike several centuries ago, prescription amounts were small (median of 20 pills per prescription).

This is welcome news; it's reinforcement that public programs focused on opioid abuse can make a difference (prescribing guidelines were promulgated by the state of Ohio and other stakeholders during the study period) and that EPs can change their prescribing habits.

Dr. Weiner commented: “It is important to recognize that the ED is a prescriber of the vast minority of opioid prescriptions. Most studies show that it is about five percent of all the opioids prescribed, and if you look at pill counts and MMEs per prescription, it's closer to two percent of the total. Still, we can be the leaders and set an example for other specialties and be cognizant that although we prescribe small amounts, we are sometimes the ones who write the prescription that get people addicted, so we need to be thoughtful about every opioid prescription we write.”

Life is full of woes, as we EPs know all too well. But by changing our opioid prescribing habits, maybe we can help our patients — and ourselves — avoid some of them.

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