Our 10th episode centers on the immune system, with some random detours, of course.

IV and IO access

At the top of the episode we discussed IO access — in general, as well as a specialized sternal IO used in TCCC. The [slightly brutal] training video I played for Kim and Alex is located here. We didn’t have time to get into it in our discussion, but IV and IO access are not without risks. A small number of IVs do result in infections at the venipuncture site (I recall a NNH of something like 3000) and here is a BMJ case report of two IOs that ended up with retained needle fragments.

FSEDs vs Urgent Care vs Hospital EDs

Approximate distribution of Texas EDs

We talked about the growing phenomenon of freestanding emergency departments and some of the business aspects that underlie their increasing prevalence. There’s a new article out, “The Impact of Conversion From an Urgent Care Center to a Freestanding Emergency Department on Patient Population, Conditions Managed, and Reimbursement” which looks at three urgent care facilities in TX that converted to FSEDs between 2014 and 2016. The study finds a huge increase in per-patient collections (not just billing, but actual income) compared to minimal change in patient demographics and chief complaints.

“Yearly number of visits decreased after conversion, while median reimbursement per visit increased (facility A: $148 to $2,153; facility B: $137 to $1,466; and facility C: $131 to $1,925) and total revenue increased (facility A: $1,389,590 to $1,486,203; facility B: $896,591 to $4,294,636; and facility C: $637,585 to $8,429,828).”

Vocab

Our vocab word this week is opisthotonus, which refers to the “back bridge” posturing that patients in the throes of tetanospasm can exhibit when the muscles of the back seize up. We also later talked about the difference between elimination and eradication of a contagious disease. The latter has a sense of permanence to it (eg we eliminated polio from the United States many decades ago, but polio has yet to be eradicated, and this could resurface in the US potentially → see: measles being eliminated from the US in the 1990s and an outbreak happening at present in the Pacific Northwest).

Image: Botulinum Neurotoxin and Tetanus Toxin, 1989

Tetanus

Tetanus is one of the deadliest neurotoxins known, at least if you define ‘deadly’ by the LD50 of the toxin. Image above can be found in this 1989 book. One reference to support the abdominal surgery comment I made is the 2017 edition of the Oxford Handbook of Infectious Diseases and Microbiology, which says: “…transmission usually occurs via introduction of spores into open wounds (particularly in IDUs), patients with recent abdominal surgery, patients with ear infections (otogenic tetanus), and neonates after cutting the umbilical cord (tetanus neonatorum).” I also mentioned that LAC+USC emergency department sees something like 10% of the cases of tetanus in the US; here’s a paper detailing some of their experience in the 1990s.

Tetanus stats: USA 2009-2015197 cases (reported to NNDS system) → 16 deaths. Case distribution (by age) not too different from US population demographics, however all deaths were in persons >55. Using 2015 as example: 20% of cases were persons reporting full vaccination status (3 doses). WHO estimates 34,000 neonatal tetanus deaths (worldwide) in 2015.

We didn’t have time to get into it, but there’s an interesting paper: “Tetanus – A Tale of 50 Years” published in Indian Pediatr., 2015. This article is a review of a prior article (and then summary of the state of where we are now). I think it’s interesting because it might hold the record for ‘longest duration between review paper and its primary literature.’ The article it reviews was published in 1965(!). Cases were classified by presence of “…lockjaw, (ii) presence of spasms, (iii) incubation period of ≤ 7 days, (iv) time interval between the appearance of first symptom and spasm of < 48 hours, and (v) axillary temperature of >99 F within 24 hours of admission. Tetanus constituted 0.5% of the pediatric admissions in the reported period. A mortality rate of 32.2% was observed … trauma and ear infection were responsible for 34.8% and 23.6% cases, respectively.” Also worth quoting: “The mortality rate was highest (66.6%) in cases where the focus of injury/infection was the face, neck and scalp, and lowest in the group with otorrhea (26.3%)” … and state of where India is at now → “In May 2015, India achieved the landmark of elimination of neonatal and maternal tetanus, certification of which requires incidence of less than 1 case per 1000 live births in all districts of the country for two consecutive years.”

On the show I mentioned otogenic tetanus. Because there was so much to talk about this episode we ended up not getting into it, but the first case I can find was reported in JAMA in 1934. This is a total tangent, but if you look at the article that appears right after this case, you’ll see it deals with 2-4-dinitrophenol as a weight loss aid! You might recall we discussed 2-4-DNP back in the biochemistry episodes. If you want to read an old school article on 2-4-DNP in weight loss [which I obviously did, since I went digging and] I found: DINITROPHENOL IN THE TREATMENT OF OBESITY. Back to otogenic tetanus → I found this article from 1980 that postulates the anaerobic environment of the inner ear is what underlies the otogenic tetanus phenomenon.

Textbook teaching is that you cannot acquire natural immunity from exposure to tetanus. I’m not saying to ignore that, but I did mention two interesting papers I found that seem to contradict this. The first, “Naturally acquired immunity to tetanus toxin in an isolated community” was published in 1985. The second, “Naturally acquired antibodies to tetanus toxin in humans and animals from the galápagos islands” was published in 1983.

R0

Image: “The basic reproduction number (R0) of measles: a systematic review.” Lancet Inf. Dis. 2017.

We talked about the basic reproduction number — R0 — otherwise known as “R-naught.” Measles is given as a prototypical example for a virus with a very high R0. The basic reproduction number is affected by a few factors beyond the ‘contagiousness’ of the disease — whether the local population has immunity (and at what prevalence), population density, the period a person remains infectious (as well as whether you are asymptomatically infectious; if you’re vomiting blood, people aren’t likely to get very close to you). Generally speaking, the inverse of the R0 tells you the vaccination prevalence needed for herd immunity, which in the case of measles is implied to be over 90%. This is why it’s so important that children who can safely be vaccinated against measles actually are vaccinated, because some kids can’t be (due to immune issues, etc) and they rely on their peers for maintaining the elimination of measles.

Droperidol

Johnson & Johnson settled for $2.2bn (and has now paid out more than $3bn) for various behavior surrounding its marketing of Risperidone — here’s an in-depth look from Steven Brill. Risperidone was a competitor to their own drug, haloperidol; with the former under patent and the latter not. Its cousin, droperidol, was also in use and (as far as I can tell) preferred to haloperidol for a number of indications by many docs.

So an interesting parallel story is the fading away of droperidol from use. It’s hard to figure out exactly why this is, but it seems to be related to a black box warning that was added to droperidol’s labeling in 2001 for a (supposed) association with Torsade de Pointes (a long QT syndrome that is a life-threatening arrhythmia). Most drugs that get warnings like this get them within a year or two of coming to market, whereas (I think) droperidol holds the record for longest time on market before black box warning (31 years). The warning was added due to a total of 277 adverse effects reports in 31 years, 11 of which were for Torsades. Five of the 11 involved doses of 240x the US dosing. Fifteen low-dose adverse events attributed to droperidol (including 8 deaths) were reported on a single day in July 2001. In total I believe there were 71 adverse events that a single day and this seems to be what caused the FDA to pay attention. Because these events were reported worldwide, and can be anonymous (and at least 32 were duplicates) it is very difficult to know how many are legitimate. Regarding the ones that weren’t anonymous and were reported by the manufacturer: “FDA regulations clearly require pharmaceutical companies to report adverse events within 15 days of becoming aware of them … The mean interval from event to report to the FDA for these cases submitted by [the manufacturer] was 7.4 years.

Within 5 years of the warning, its usage had dropped by 90% in the US. This seems at odds with the demand for it I’ve observed, however, as most EM docs speak highly of it, and continue to use haloperidol (which also prolongs QT). Ironically, for antiemetic use, droperidol was replaced by 5HT3 antagonists, primarily ondansetron, which causes QT prolongation. In 2003, the FDA reconvened an advisory committee to address the black box warning. Despite expert testimony from cardiologists questioning the validity of using QTc as a surrogate marker for torsades, and a number of peer reviewed studies and independent investigations, the warning remains. To quote a 2015 Annals of Emergency Medicine paper:

“In comparison, published, peer-reviewed literature in the years leading up to 2001 appears to have produced neither a single case report nor a prospectively documented event of ventricular arrhythmia or sudden death with the drug, despite one review of 74 droperidol trials with more than 13,000 subjects, another of 67,000 droperidol uses, and multiple comprehensive literature reviews including case reports and observational data. Meanwhile, the MedWatch reports have spawned at least 5 external reviews by 4 independent research groups, all of whom challenge the black box warning as unwarranted.”

 Here is another good review of much of the safety evidenceSome information not cited above was gleaned from this Yale thesis.

Anti-venom

Alex mentioned a couple of different article. Here’s one from the Journal of Clinical Toxicology comparing FAB and F(AB’)2. The article in Science, “For Mexican Antivenom Maker, U.S. Market Is a Snake Pit” was also mentioned [PDF]. He also mentioned a person bit by a rattlesnake in Yosemite; the article about that is here.

Andexanet Alfa

We spent a few minutes discussing the newly released “full study report” on andexanet alfa. [The complete write-up of our discussion on the DOACs and this reversal agent can be found in EP009]. Not a lot has changed since their report that included 67 patients rather than the 352 in this report. There is some data-dredging going on, and it’s interesting to note that the post-marketing RCT they are conducting is focused on ICH rather than all types of bleeding; their data dredging showed no hemostatic efficacy overall, but a mild efficacy in ICH. Whether this is because it works better in ICH, or is just easier to show, is hard to say.

The current standard of care in serious bleeding with DOACs is PCC. There’s not a ton of strong, direct evidence to show whether this works or not. Low to medium quality evidence suggests that at doses of 50IU/kg PCC or aPCC are effective. This is worth mentioning since the cost of FFP is $500, the cost of PCC is $5,000, and the cost of andexanet alfa is $50,000 (for a high dose bolus + one infusion). The RCT they’re conducting, due to be finished in 2023, is “evaluating the efficacy and safety of andexanet versus usual standard of care in patients with intracranial hemorrhage anticoagulated with a direct oral anticoagulant.” Unfortunately they don’t define what the “usual standard of care” is, and the emergency medicine resources I’ve used while studying say PCC, but it’s possible they will compare against something else. Time will tell, I guess.

For some papers on DOAC reversal, see the following:

https://jintensivecare.biomedcentral.com/articles/10.1186/s40560-018-0303-y
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.029017
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078696
https://onlinelibrary.wiley.com/doi/full/10.1111/jth.12599
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.114.013445
https://link.springer.com/article/10.1007/s11239-015-1297-0 (review of all relevant studies through 2016)
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.021831
https://link.springer.com/article/10.1007/s11239-013-0967-z (DOAC half life data)
https://www.ncbi.nlm.nih.gov/pubmed/2814925 (1989 paper on various factor levels and effect on prothrombinase)


— Episode credits —

Hosted by Addie, Kim, and Alex. Audio production and editing by Addie. Show notes written by Addie. Theme music compositions (Too Cool, and Laserpack) by Kevin MacLeod of incompetech.com, licensed under Creative Commons: By Attribution 3.0 License.