Category Archives: snake

Copperheads don’t cause coagulopathy

CopperheadInLeavesCU“. Licensed under Public domain via Wikimedia Commons.

Copperheads are common across the southeastern US, and are responsible for a significant number of crotalid envenomations in areas where they are endemic. However, they have the least potent venom of all the pit vipers, and often bites are self-limiting. Prior to development of CroFab, copperhead bites were generally not given antivenom, as the risks of the Wyeth product were felt too high for minimal benefits. Now, CroFab is felt to be safe enough to mitigate even mild symptoms of copperhead envenomations.

However, physicians typically work up copperhead bites the same way they do the other crotalid species. This includes chemistry, complete blood count, and coagulation studies. And often patients are admitted for serial checks of these lab values even if there are no significant physical exam findings.  But are these really necessary when the snake is clearly identified as a copperhead?

These authors suggest that it isn’t. They examined more than 10 years of data from their 2 hospitals in St. Louis and found 106 “probable” or confirmed copperhead bites. Of these, 6 had abnormal coagulation studies, all were minimally outside of normal limits. None had bleeding complications either. Thus, the utility of coagulation studies in copperhead bites is suspect.

So can we stop checking coags on these patients? It’s a decent consideration, in the absence of evidence of coagulopathy. More importantly, patients don’t need to be admitted for serial coagulation studies if the snake in question is definitively a copperhead.  Perhaps checking an initial lab, and if it it’s normal, send them home if no other concerning symptoms. However, if you’re considering giving antivenom, you’re not saving any money by not checking, and you’re probably not sending that patient home.

Lack of Coagulopathy After Copperhead Snakebites

Stroke after crotalidae antivenom

When it first came out, crotalidae polyvalent immune Fab (CroFab), was seen as a godsend by many. It didn’t cause anaphylaxis or serum sickness to nearly the same degree as the old product. There was plenty of safety data, so it started to be used in less severe cases that before, antivenom would be withheld because the risks outweigh the benefits. And now there are case reports like this.

Sean Bush, who just happens to have been on the tv show “Venom ER”, collected these two cases of acute ischemic stroke after treatment of snake bites with CroFab. Both were probably Southern Pacific rattlesnakes (one definitively identified, one presumptive).

Crotalus viridis Southern Pacific Rattlesnake Juvenile” by Matthew Robinson from Santa Monica, USA – baby rattle. Licensed under CC BY 2.0 via Wikimedia Commons.

The first case was a 50 yr old, bitten on the leg, with pain, swelling, shortness of breath, and parasthesias. He got the initial dose of 6 vials, then had his compartment pressures checked. That got him another 12 vials. Later that evening, he showed classic signs of CVA with slurred speech, right-sided weakness, and right facial droop. Labs remained normal, CT was negative, and tPA was withheld due to risk of hemorrhage. However, he got 6 more vials of antivenom because of neurologic symptoms. MRI showed devastating bilateral lesions, and the patient expired. Autopsy showed emboli in the lungs, heart, and multifocal infarcts of the CNS.

Case 2 was a little different. He was 17, bitten on the finger, and had pain, swelling, and parasthesias of that extremity. He got 6 vials initially, then got 20 more over the next 3 days. On that third day, he showed classic cva symptoms with left-sided facial droop, and total left-sided body weakness. His CT was negative, but again no tPA was given (for good reason). MRI showed multiple infarcts as well, but not as globally as the first.

Both patients were tested for hypercoagulability and were negative. So what gives? Why did two patients in the middle of a classic crotalidae envenomation develop ischemic CVAs after treatment? Fibrinogen and platelet levels were normal in both patients, indicating that they weren’t coagulopathic when given the CroFab. INR isn’t mentioned in the paper, presumably it was normal. The key aspect in this case series is the species of snake itself. One southern pacific rattler (Crotalus oreganus helleri) was discovered to have procoagulant activity in its venom, and among crotalidae, they have some of the most varied venom studied to this point. And it has been demonstrated that CroFab doesn’t have activity against rare, or small proteins that aren’t immunogenic.

Because it is unlikely that CroFab includes fabs specific for this procoagulant protein, in a patient envenomated by a southern pacific that was producing that protein, the net effect would be likely be procoagulation, thus causing the thrombotic phenomena shown. However, we can’t be so sure it is just this snake species, as the references in the paper have numerous other cases of ischemic strokes after multiple other types of snakes.

Yes, these are rare events, but neither of those patients appeared to be so sick that they would have died without antivenom. Perhaps judicious application of antivenom should be considered until the etiology of these events is fully understood.

Catastrophic Acute Ischemic Stroke After Crotalidae Polyvalent Immune Fab(Ovine)-Treated Rattlesnake Envenomation

Stop skin testing

This post came from a question received in our simulation lab a couple of weeks ago. Mainly, there was a simulated patient with latrodectus envenomation, and there was a fair amount of discussion about skin testing prior to administration on antivenom. Now, when I say discussion, what really happened was some faculty said skin testing was recommended by the package insert and all of their prior readings, whereas the residents were simply asking “why?” Then both groups practiced their google-fu and were able to come up with abstracts to support their viewpoints.

So, yet again, it seems there might be a generational gap between evidence and practice, so I figured I would try to answer their question here. And yet, when I went to search, there haven’t been a large amount of RCTs for skin testing, which isn’t shocking for the toxicology literature.

However, there have been a few decent case series that do not show a benefit to skin testing, as well as a few case series that demonstrate the safety profile of latrodectus antivenom. Putting these together, one could logically make the case against skin testing for latrodectus antivenom. However, there have now been two case reports of deaths from latrodectus antivenom use, one in a young woman with a history of asthma who received an undiluted push dose of antivenom, and more recently a man, also with asthma, who received a diluted dose of antivenom but died after experiencing anaphylaxis. The authors feel his death was likely from PE, but it still happened secondary to antivenom.

This article from Thailand was a retrospective review of snake bites who received antivenom. Over a little more than nine years, there were a total of 254 cases, 211 of which received skin testing. Ten of these patients had positive skin tests, and received different treatment. Desensitization was used in 5, and “close observation” was used in the other 5, but they still received undiluted antivenom. There were no reactions in any of the 10 patients with positive skin tests. Conversely, 7 patients with negative skin tests had reactions to the antivenom, and two who did not receive skin testing also had reactions. So the sensitivity of skin testing in their paper is 0%, and the specificity was 96.4%. Not terribly helpful for making decisions in management.

The good news for the practicing physician is that the weight of the current evidence has led the WHO to recommend against skin testing (at least for snake antivenom) as it leads to delays in treatment and does not help in decision making.

Skin and conjunctival “hypersensitivity” tests will reveal IgE mediated Type I hypersensitivity to horse or sheep proteins. However, since the majority of early (anaphylactic) or late (serum sickness type) antivenom reactions result from direct complement activation rather than from IgE mediated hypersensitivity, these tests are not predictive. Since they may delay treatment and can in themselves be sensitising, these tests should not be used [level of evidence T].

They do have the caveat that they only recommend antivenom treatment in patients who the benefits of said treatment outweigh the risks of allergic reactions.

My personal practice is to not perform skin testing. There is a very small number of patients who I feel need antivenom that I would withhold treatment based on a positive skin test. And since preventive treatment has not been proven effective, again it would only serve to delay definitive care. If I had a patient with a known severe allergy history, I would probably pretreat them (or concurrently treat them), but I would also get epinephrine and advanced airway equipment to the bedside. The harms and costs of a single dose of steroids and antihistamines are exceedingly low, and you have less of a risk of some “expert” saying you were acting cavalier.

Low incidence of early reactions to horse-derived F(ab′)2 antivenom for snakebites in Thailand

Of note, skin testing doesn’t appear to work for drugs either, so maybe there’s no point in doing it for anything emergent. In this paper, the skin test for cephalosporins had a sensitivity of 0%, specificity of 97.5%, negative predictive value of 99.7%, and a positive predictive value of 0%. Nobody with positive skin tests reacted to the medication, and 4 people with negative tests did have immediate reactions.

Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: a prospective study with drug challenge.