Redback spider bites are of decent medical importance, if you live in Australia or any of the places they’ve been carried to by humans. Their venom inflicts you with pain that can be local, regional, or generalized. It can also cause systemic effects such as nausea, vomiting, headache, or malaise. Due to this, Australian researchers have carried out multiple studies on the utility of redback antivenom for treating the effects of bites.
This one, recently e-published in Annals of Emergency Medicine, is a follow-up RCT to a prior study. This study compared antivenom to placebo. That prior study compared IM to IV antivenom, and was also an RCT. It found statistically no difference between the two routes, so they used IV dosing for the second study.
Methodologically this paper is sound. They describe their power calculation, and the blinding is pretty impressive. They even used an independent analyst to check the data before the blinding was removed. Sadly, they had to close the trial 16 patients early, due to lack of funding. They simply couldn’t afford to supply the 20 study hospitals with another set of test vials.
One drawback is that the spider wasn’t identified nearly 1/4 of the time. This is less of a concern than in, say, my patient population, where the MRSA spider is endemic. Aussie clinicians are fairly familiar with redback envenomations, and the other venomous spiders have distinct envenomation syndromes.
For their primary outcome of improvement in pain at 2 hours, there was a 10.7% difference between placebo and antivenom (23 vs 34%). Their second primary outcome was resolution in systemic effects at 2 hours, and there was only a 4% difference (22% placebo, 26% antivenom). Neither of those outcomes reached statistical significance. Secondary outcomes were improvement in pain at 4 hours and 24 hours, rescue treatments (second doses of unblinded antivenom or opiates) as well as use of opioids after discharge, followup medical care, and serum sickness. There was no significant difference in pain measurements at 4 and 24 hours, use of rescue treatments, or followup medical care. There were only 4 acute hypersensitivity reactions, all in the antivenom group. Interestingly, there were 5 cases of serum sickness in the placebo group (even after those who got rescue antivenom were removed from the count).
Thus, for Redback spider antivenom the NNH is 25, while the NNT is only 10. For pain secondary to redback bites, antivenom doesn’t work, but pain meds don’t seem to either. The authors note that more RCTs need to be directed towards identifying treatments that do work. Isbister himself has said that this has changed his practice to the point that he won’t use redback antivenom anymore.
Since latrodectus species are present on almost all continents (sorry Antarctica), and there is a fair amount of cross-reactivity among multiple species, should we apply this to all latrodectus spiders? In a word, no. Redbacks (L hasselti) cause pain, but aren’t as toxic as North American (L mactans and L hespersus) or European (L tredecimguttatus) spiders. Reports of death from redbacks are incredibly rare, and treatment is directed towards simply treating the pain. So while not using antivenom to treat pain is prudent, current recommendations for the US black widow antivenom are to prevent untoward outcomes from severe envenomations in the young and those with comorbidities. It is hard to power a study to show benefit in such rare events. Antivenom isn’t cheap, and it isn’t without risks. It’s basically the tPA of the toxicology realm. And it probably has just as much controversy.
It looks like it is time for @precordialthump to update his CCC on Australian antivenoms.
Randomized Controlled Trial of Intravenous Antivenom Versus Placebo for Latrodectism: The Second Redback Antivenom Evaluation (RAVE-II) Study.
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.
Short case report from the Netherlands today. It involves a 22 year old woman who went to Italy on vacation, and one night woke up with left ear pain. This progressed to a small vesicle, then to swelling of the entire left side of her face. She was given antihistamines, but 2 days later had continued edema, worsening ear pain and a rash of her entire body. She also developed the characteristic red, white, and blue discoloration of her ear at that time. She was given higher doses of antihistamines, but no other treatment per the report. She developed necrosis by day 12.
Once she returned home, she went to a plastic surgery clinic where she received a partial ear reconstruction using costal cartilage and a full thickness graft. The authors wrote the case up as the first documented instance of cartilage necrosis due to (presumed) recluse bite.
The report then does a good job of describing proper recognition and treatment of recluse bites, as has been discussed here before. Pretty decent write-up and excellent figures by the Journal of Plastic, Reconstructive & Aesthetic Surgery.
Partial ear necrosis due to recluse spider bite