I apologize for the gap between my last post and now. I’m in the middle of exploring some other potential blog formats/hosts. Speaking of gaps…
A recent emergency department consult brought up an interesting and controversial topic within the realm of medical toxicology. The case, in brief, was a middle aged patient with metabolic acidosis, elevated anion gap, and elevated serum osm gap. He presented to the ED with suicidal thoughts, admitting to heavy recent EtOH use and consistently denied even the chance of ingesting any other liquid or alcohol. The primary history takers in the ED thought his history was consistent and believable. The emergency providers were admitting the patient with diagnoses of alcoholic ketoacidosis, lactic acidosis, agitation, hypertension, tachycardia, and dehydration. The patient had a history of heavy alcohol abuse, a present-but-low serum EtOH concentration and normal renal function, The question that came up during the discussion between the admitting physician and the ED was about whether or not a “toxic alcohol” screen (I put this in quotes because it always annoys me that according to that test name apparently ethylene glycol and methanol are toxic but ethanol isn’t) should be done in this context of metabolic acidosis, elevated anion gap, and osm gap. The list of core questions that need to be answered here are (and this list is not all-inclusive):
1) Why is there a lactic acidosis?
2) Is the anion gap explained by the lactate and AKA?
3) Is the osm gap explained by the lactate and AKA?
4) Is an osm gap reasonable and accurate enough to use to make decisions?
5) Finally, in the case of a middle-aged patient with AKA, lactic acidosis, elevated anion gap, elevated osm gap, do you need to rule out ethylene glycol and methanol as causes, and do you need to order a “toxic alcohol” screen in order to do that?
The following is a short (and again not by any means all inclusive) list of articles that I’ve collected and used to help answer questions in this setting in the past. Check them out, or just keep them somewhere for yourself, and I’ll come back to give my version of how to approach this issue in the next post.
If you’re tired of Spice and Bath Salts, give Pump-It Powder a shot…
"Pump-It Powder", of course sold as something not for human consumption, is popping up more frequently lately. Patients exposing themselves to this substance seem to present with symptoms similar to other sympathomimetic and occasionally hallucinogenic substances. The not-yet-confirmed-but-very-likely-main-ingredient is methylhexanamine, an amphetamine-type substance that has been the functional ingredient in a number of substances used for intoxication and stimulant doping in the past. Generically you’ll see it called methylhexanamine and also dimethylamylamine, or DMAA.
For agitation related to intoxication with Pump-It, just treat with fluid, benzos, etc, just like you would for cocaine, meth, bath salts, etc.
Keep your eyes open for this…more to come.
Another possible antidote for poison-induced cardiogenic shock…
In an attempt to keep you up to date on what’s going on in the world of antidotes for cardiogenic collapse caused by drugs, I’d like to call your attention to another couple articles and an antidote that’s probably new for you. This will be something to add to the list in your head to somehow organize with fluid, calcium, high dose insulin, intralipid, glucagon, pressors, levosimendan, l-carnitine, methylene blue, etc.
Dr. Allan Mottram is a medical toxicologist and emergency medicine physician at the University of Wisconsin. He teamed up with a couple of medical toxicologists out of Chicago (where he trained), Drs. Sean Bryant and Steve Aks, for this work. The first study (here’s the PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20724913) looked at high dose cyclodextrin (CD, sulfobutylether-beta-cyclodextrin to be exact) in the setting of verapamil toxicity in rats. The rats treated with the high dose CD actually did worse. They theorized that this could have been due to the hyperosmolar load from the CD, and that further study was needed at lower doses.
The second study (http://escholarship.org/uc/item/07p476t8) was the follow up and looked at a lower concentration of the same CD. This showed promise in that there was a statistically significantly increased time to asystole in the CD-treated verapamil-toxic rats.
CDs are hydrophilic complexes that have a hydrophobic core. Lipophilic molecules fit into that core. They are often used to modify solubility and stability of drugs. Using CDs as antidotes has been done before (with rocuronium), but even in the nerdy world of toxicology this is not something commonly discussed, and certainly not often tried/studied. I look forward to more work on this subject, as CD use in the setting of overdose-induced cardiogenic shock is not ready for prime time yet, but shows some definite promise.
Another successful use of lipid rescue..
There is another nice success of lipid administration in the literature, this time in the articles in press section of The Journal of Emergency Medicine. The offending drug was a TCA, dothiepin, and the patient came in very sick.
The time course of the patient care is pretty compelling case for the cause and effect relationship of the lipid making the patient better, and it seems like an appropriate usage of the rescue therapy.
I have a couple of issues with how this case and discussion were presented. The first is that there was scant discussion of lipid solubility, what that means, and the maybe more concise parameters of the octanol/water coefficients of log P and log D. It’s possible that they were severely limited on writing space, as often happens in case reports, so they can get an easy pass on this one. The second issue, and this one is the slightly more annoying one, is that at multiple points in the case presentation and discussion they reference giving sodium bicarbonate, and each time they insinuate that the only reason for its administration is for the bicarbonate portion of it to alkalinize the patient. They don’t reference the huge QRS (they include an ECG, and the QRS is really big) and they don’t make reference to attempting to narrow the QRS with the sodium portion of the sodium bicarb. Sodium bicarb in this setting certainly can transiently correct some acidemia, and that’s helpful because of the protein-binding implications (as the blood pH goes down, the protein binding goes down, leading to more free TCA circulating in the patient), but immediately after administration the more important effect is the QRS narrowing.
Confidence Interval For My Breakfast Choices?
Every now and then I’m going to start spicing up your life with a little statistics, because everyone needs a little excitement from time to time, right? I won’t get crazy and nerdy with it, but I realized that when I bring up studies I will often times mention statistical terms that might need some explanation, depending on where you are in training/practice.
First off, I apologize for leaving you without a post for the last couple of weeks. I’m really not sure how you’ve been able to function during this time. For full disclosure, Twin Cities Tox got a vision upgrade, but it was done using the non-flap all laser PRK version rather than Lasik (google PRK if you desire further details; the interweb is back open today and ready to inform you on searches like that) so my visual recovery time has taken a while.
Now that we have that out of the way, let’s move on to the meat of the discussion, which is a basic explanation of confidence intervals. This is becoming more and more often used and desired by some of the prominent journals (Annals of Emergency Medicine, for example), and you should have some understanding of it. A confidence interval is basically a percentage of certainty (95% is most common in our scenario) that an upcoming unknown parameter will fall between a certain set of values, with that interval based on a set of previously measured similar parameters. It is truly an assessment of sampling, and ideally projects the reliability of that sampling projected onto potential future sampling by saying “this is the interval computed from the sampled data, which, if that study were repeated multiple times in the future, would contain that future sampling data 95% of the time”. In it’s most basic form the main thing in a study that affects a confidence interval is the number of samples, with a higher number of samples offering a better (narrower) CI. Really, the spread of the data matters as well, but ignore that for now.
If I told you in general I have smoothies for 71% of my breakfasts, and bowls of oatmeal for 29% of my breakfasts, you would probably just say “ok” because you don’t give a shit what I eat for breakfast. If I were presenting that breakfast breakdown as a study, however, you would have to ask more about my sampling of that data in order to verify it. This also applies if you’re making up a disturbing instance where you give a shit about what I eat for breakfast, or even more disturbing would be if you’re not making it up, and you really do care.
Here are a couple versions of sampling, which drastically change the 95% CI of the data (this is crude but accurate calculation, everyone but statisticians should be fine with this).
In the first scenario I tell you that I got that breakfast data from sampling one week, or 7 mornings. I had 5 days of smoothies and 2 days of bowls of oatmeal. That data gets presented like this: Smoothies 71% (95% CI 30%-95%); Oatmeal 29% (5-70).
In the second scenario I tell you I’ve been sampling for a year. That’s 259 smoothies and 106 bowls of oatmeal. Now I get to report: Smoothies 71% (66-76); Oatmeal 29% (24-34).
In the second scenario my sampling is much more acceptable and potentially accurately predictive because the intervals are narrower and don’t cross each other. If I’m looking at just the week of sampling, I can report what happened in raw terms (5 S, 2 B of O, for 71% and 29% respectively) but I can’t make a comment on what I do in general, even outside that sample. That’s what CI allows me to do.
Make any sense? I hope so, because I’m going to hit on CI in the next couple days with a study example.
It sounds like a direct-to-Netflix horror movie plot — a cheap, addictive drug available in a foreign land, that turns the user’s skin a scaly green color. Soon it rots the flesh, causing the user’s skin to emulate that of a crocodile, leaving bone and muscle tissue exposed to the world. But the Russian drug known as krokodil is real.
Warning: Disburbing images of the effects of Krokodil below. This article may be shocking or upsetting for some people. Please proceed with caution.
Top image via fritscdejong on Flickr.
YouTube videos emanating from Russia displaying the after-effects of Krokodil use have been available for months. The clips often spotlight the gore factor, displaying the gangrene, exposed bones, and scale-like skin that lent the drug its name. What makes people use a drug that will destroy their body, to the point where their bones are exposed and require amputation? Why is usage (so far) contained to Russia?
What is in Krokodil?
Just as crack is the broke addict’s cocaine, krokodil is a substitute for a much more expensive drug, heroin. The chemical behind krokodil, desomorphine, was available as a morphine substitute shortly after laboratory synthesis in 1932. Desomorphine is 8-10 times more potent than morphine. The medicinal use of desomorphine was concentrated to Europe, particularly Switzerland. The synthetic opiate has a structure nearly identical to heroin.
Codeine, a readily available narcotic, can be turned into desomorphine in a relatively easy series of chemical reactions, and then injected intravenously by the user. Whereas heroin may cost $150 US and up per use, krokodil can be obtained for $6-$8 US per injection.
How is Krokodil made?
The problem is not necessarily desomorphine addiction, it’s the fact that krokodil users are unable to make a pure enough final product prior to use. When performed in a lab, the transformation of codeine into desomorphine is a rather easy, three step synthesis. When cooked in a kitchen lab, however, krokodil users often lack for materials, and thus use gasoline as a solvent along with red phosphorous, iodine, and hydrochloric acid as reactants to synthesize desomorphine from codeine tablets.
The final product is often an impure, orange-colored liquid, with this impurity causing skin irritation, a scale-like look, and eventual destruction of the skin. This is likely due to the presence of hydrochloric acid still in the final liquid solution prior to injection, with red phosphorous, obtained by solvating and removing the “striker” portion of matchboxes, playing a role in furthering sickening the user. Once the skin around the injection site is damaged, the area becomes a target for gangrene. This leads to skin decay around the injection site, and, in time, the skin sloughs off, often exposing the bone below.
Addiction is a full time job
The high associated with krokodil is akin to that of heroin, but last a much shorter period. While the affects of heroin use can last four to eight hours, krokodil users are lucky to get an hour and a half of bliss, with the symptoms of withdrawal setting in soon after. Krokodil takes roughly 30 minutes to an hour to prepare with over-the-counter ingredients in a kitchen.
The short time table causes addicts to be trapped in a full time, twenty-four hour a day cycle of cooking and injecting in order to avoid withdrawal. Once someone becomes addicted, it is common for the individual to die within two-three years of heavy use from exposure and associated health issues, with many dying within a year.
Why is use prevalent in Russia?
The major reason krokodil use is confined to Russia is due to the availability of codeine for purchase without a prescription — anyone can walk into any pharmacy and buy tablets containing the starting point of krokodil synthesis. Access could quickly be cut off by making codeine containing analgesics a prescription-only pharmaceutical in Russia. This has been met with backlash from citizens, as most believe that krokodil users will find another avenue for codeine, while preventing “proper” users from obtaining the analgesic tablets.
A lack of government infrastructure also plagues krokodil users. Russia lacks a significant state-sponsored rehabilitation system, nor have they made any significant moves to ban the over the counter sale of codeine tablets. Speaking on this subject, Viktor Ivanov, head of Russia’s Drug Control Agency, said:
A year ago we said that we need to introduce prescriptions […] These tablets don’t cost much but the profit margins are high. Some pharmacies make up to 25 per cent of their profits from the sale of these tablets. It’s not in the interests of pharmaceutical companies or pharmacies themselves to stop this, so the government needs to use its power to regulate their sale.
Withdrawal symptoms can last up to month, making it a rather difficult habit to kick. It takes a phenomenal amount of will power to put up with the physical pain of withdrawal for a month than go to the kitchen and make another dose. Rehabilitation systems are present, with the vast majority religious-based due to the lack of government involvement.
Apart from wanting to name this article In Soviet Russia, Drugs Eat You, there is not a lot to laugh about in regards to krokodil. It is a debilitating, body-destroying drug that’s consumed predominantly by the poor. Reports of usage in Germany have also surfaced as of October 2011, where codeine drugs require a prescription. Codeine products have been considered “prescription only” narcotic for decades in U.S., the UK and Sweden. But pills containing codeine can still be purchased without a prescription in a Canada, Australia, Israel, France, and Japan. We may soon see the devastating effects of krokodil in these regions too.
Images of Krokodil use courtesy of stopnarkotik.com.ua and youtube user kay8x. Sources linked within article.
Miracle weight loss pill (it sounds terrible)…
I don’t talk much about “health” products such as the different available weight loss agents, so I’m going to start doing that every now and again. I’ll kick it off with a brief discussion of Redotex, a weight loss supplement with FDA warnings against it since 1987. It’s a smorgasbord of goodness, including atropine, d-norpseudoephedrine, aloin, diazepam, and triiodothyronine (T3). That sounds great. Why would you live a lifestyle of exercise and balanced diet when you could just load up some antimuscarinics, adrenergics, benzos, and thyroid stim? I prefer the inefficiency of going to the gym, but if they made this stuff in animal shaped gummi-pills, you could count me in.
Redotex is not easily available in the US, but it apparently is widely available in Mexico. There are 2 pubmed-indexed hits that you’ll come up with on a search for “redotex”, and both of them are Mexico-related. One is a poison center data survey study with a bunch of cases clustered around the Texas/Mexico border (Forrester MB. Hum Exp Toxicol 2010) and one is a case report of a woman who purchased her Redotex in Mexico prior to consumption (Cantrell L. J Emerg Med 2011). It seems that there have been no severe outcomes from exposure, or at least none reported. Not shockingly, some hypertension and tachycardia can probably be expected from ingestion.
Poisonings kill more than car crashes... -
This is slightly old data (2008), but it’s an article from today’s health section of the New York Times.
My last bit about cyanide for a while…
Whenever we get the opportunity to manage a unique case, one of the benefits is that it can encourage some great learning. The three options of cases like this are the same options of cases that make CPC competitions at conferences good.
The first option is the usual presentation of an uncommon case. This is the most fair because if we know our zebras, it’s no problem to move forward with management. The second option is the unusual presentation of the common case. This is slightly harder, because it’s so easy to get anchored to uncommon things to try to explain the clinical scenario that we overlook the possibility of an odd presentation of something we see all the time. The third, and most ridiculous, option is the unusual presentation of the uncommon case. It’s very difficult to nail these cases in actual clinical practice or in the setting of a CPC competition.
The cyanide tidbit for today would likely fall into that third category. Did you know that cyanide toxicity can cause hyperammonemia, and that the same mechanisms that cause this are likely at the heart of why patients exposed to cyanide often times lose consciousness very early on in the course? If you knew that, you’re a better man (or woman) than I. In a grass roots poll of some of the tox folks around here, the most knowledge any of us had about this was maybe hearing something about ammonia and cyanide and not having any idea about anything further. It was good learning for us during a recent case (that, as it turns out, was likely not a cyanide toxicity in the first place).
I don’t want to belabor this point, because it’s both super nerdy and might only come up once in each of your careers, but I think it’s interesting so here goes…
Hiro-aki Yamamoto published a study in 1993 in the Bulletin of Environmental Contamination and Toxicity entitled Relationship among cyanide-induced encephalopathy, blood ammonia levels, and brain aromatic acid levels in rats. It is a difficult read, I think because the translation to English was not the smoothest process, but it’s gold as far as tox biochemical nerdity. This paper was actually a follow up to a manuscript he had published in 1989 on the topic, and expanded on his original thoughts.
The summary is that it seems as though the combination of the hyperammonia that develops from indirect disruption of the urea cycle combined with dramatic increases in aromatic amino acids like tyrosine and phenylalanine (but not aliphatic amino acids) causes the loss of consciousness. The author’s theory is that the high levels of ammonia function to assist in increased absorption of the aromatic amino acids resulting in inhibition of the release of neurotransmitters from synaptic terminals.
I realize that stuff is very specific, but it’s a little satisfying for me to have at least some explanation for why folks with cyanide toxicity pass out so quickly, when that’s not always the case in patients with presentations of other pathophysiology causing acidemia and inhibited cellular aerobic function.