Bark Scorpion Sting: Indications for Anascorp and dosing controversies


AnascorpThe genus
Centruroides, also known as the Bark Scorpion, is found throughout the southwestern United States and northern Mexico. Many emergency medicine practitioners in the Southwest are exceptionally familiar with the treatment of envenomation from Centruroides as a quarter million are reported annually1,2. Although typically mild envenomations occur in adults, children and the elderly are at increased risk for severe complications3. The toxic syndrome consists of a sympathetic and parasympathetic storm that can result in myocardial damage, involuntary jerking, wandering eye movements, and most threatening – loss of airway.

Grading of envenomations

Centruroides envenomations are graded by these symptoms, moving from grade I-II (considered mild) to grade III-IV (considered severe)3.

Table adapted from 3
Grade Signs and Symptoms Treatment
I At the site of envenomation:

  • Pain +/- paresthesias
  • Positive tap test (severe pain increased with touch or percussion)
1. Support the airway
2. Provide pain control
3. Apply ice to site of sting
II Grade I AND:

  • Pain / paresthesias remote from the site
Same as Grade I
III Any of the following:

  • Somatic skeletal neuromuscular dysfunction
    • Jerking of extremities
    • Restlessness
    • Severe involuntary shaking and jerking, which may be mistaken for seizures
  • Cranial nerve dysfunction
    • Blurred vision
    • Wandering eye movement
    • Hypersalivation
    • Trouble swallowing
    • Tongue fasciculation
    • Upper airway dysfunction
    • Slurred speech
Same as Grade I/II PLUS consider the following:

  1. IV benzodiazepine infusion
  2. Centruroides antivenom, if available
IV Both cranial nerve AND skeletal muscle dysfunction  Same as Grade III

Who should we treat with antivenom?

In the time before antivenom, morbidity and mortality in severe cases were much higher. Treatment consisted of supportive care, typically involving benzodiazepines, opiates, and intubation, if necessary4. For patients receiving large total doses of benzodiazepines for neuromotor dysfunction, there comes the additional risk of respiratory depression, intubation, and an admission to the intensive care unit. In 1965, the production of whole immunoglobulin antibodies derived from goats, achieved exceptional treatment success rates. This antivenom was not FDA approved and came with relatively high rates of anaphylaxis (3.4%) and delayed serum sickness (61%), which made many practitioners continue to rely on supportive care4,5. In 2001, production of this antivenom was ceased and the stock was depleted by 2004.

Anascorp (Scorpion [Centruroides] Immune F(AB)2) was approved in 2011 by the FDA and is considered standard treatment for grade III-IV envenomations. This product has been available in Mexico (Alacramyn) for many years prior to FDA approval and is dosed more conservatively than Anascorp.

Anascorp Dosing: The Anascorp package insert recommends an initial dose of 3 vials, followed by additional vials as needed with a maximum of five total vials3,6. Anascorp is equine derived and has a low rate of serum sickness (0.5%). No cases of true anaphylaxis have been reported6,7.

The evidence is certainly not robust in determining which patients will benefit most from antivenom treatment and tends to cause variation in standard practices. This has become a point of interest for pharmacy departments as the cost of Anascorp is ~$3,000-4,000 per vial, and we prefer not to break the bank for patients with astronomical medical bills. There are reports of hospitals in the United States charging between $7,950 to $39,652 per vial8. This has caused some institutions in the Southwest to establish protocols administering one vial at a time, with a “watch and wait” methodology before providing additional vials.

Should we deviate from FDA instructed dosing?

This would not be the first drug to be administered “off-label” in the emergency department (i.e. ondansetron in the ED, PO naloxone, IV olanzapine, ketamine takedown, etc.). The trials that granted the approval of Anascorp evolved to using 3 vials initially, but is it really necessary?

Currently, the one study that has citable data attempting to answer this question is in the process of being published; fortunately, the authors presented their results as a poster at the American College of Medical Toxicology conference in 2015. Their study was a retrospective review looking into pediatric patients with at least a grade III-IV envenomation and compared 3 groups: those not receiving Anascorp, those receiving the FDA approved dosing regimen, and those receiving conservative dosing with one vial initially, followed by additional vials if needed based on symptoms9.

* FDA Dosing vs Conservative Dosing
† No Anascorp vs FDA Dosing & Conservative Dosing
No Anascorp FDA Dosing Conservative Dosing p value
# Patients (n=156) 58 16 82
Mean Age 5.7 years 2.5 years 4.0 years 0.001; 0.024*
Grade IV 24 (41%) 14 (87%) 76 (93%) <0.001
Respiratory Distress 3% 56% 38% <0.041
Mean Vials Used 0 3.25 1.83 <0.001
Mean ED LOS 261 min 253 min 259 min 0.839
Hospitalization 3.4% 0 8.5% 0.167
Intubation 0 0 2.4% 0.607
Aspiration 0 0 2.4% 0.607

These results illustrate there were no significant differences between clinically relevant outcomes, regardless of treatment group. It should be noted that there were much higher rates of respiratory distress in the 16 patients from the FDA Dosing group, suggesting a “sicker” population. However, 93% of the patients in the Conservative Dosing group were considered grade IV envenomations. Should respiratory distress be used as a better indicator for treatment? This remains to be answered, but it does question the need for 3 vials from the initial onset in grade III-IV envenomations in pediatric patients.

The original protocol for Anascorp phase 2 and 3 trials started with 1 vial followed by additional vials based on symptoms every 30 minutes. They found increased treatment adverse events with 1-2 vials (42.5%) versus patients receiving 3, 4, or 5 vials (24.5%, 28.3%, and 35.8%, respectively). Thereafter the protocol was changed to start with 3 vials10.

Pharmacology

Anascorp has an exceptionally long half-life of  about 160 hours and an area under the curve (AUC) of 706 µg*hr/mL to match6. After administration of 1 vial of antivenom, serum venom levels have been noted to drop from 1,000-4,000 pg/mL to 200 pg/mL within 30 minutes and become undetectable within 2 hours11. In Mexico, antivenom costs about $100 per vial and the dosing regimen is performed 1 vial at a time, followed by observation for 30 to 60 minutes before repeating. Additionally, in Mexico the antivenom is used frequently for lower severity stings (grade I-II), likely due to the low cost12.

Challenges and Final Thoughts

Although the FDA package insert states to give 3 vials initially, the FDA is limited to the studies submitted for approval. It can also be an uphill battle changing the prescribing habits especially of providers who have ordered 3 vials of antivenom to a scorpion envenomation patient and had them practically symptom-free within minutes to a few hours. This is followed by smiles, high fives, grateful patients and families, a discharge home from the ED, and lastly, but certainly not least, a massive bill.

The literature and practice in neighboring countries appears to suggest that using 1 vial and watchfully waiting is a viable strategy with similar outcomes. Next time you have a patient with a grade III-IV Centruroides envenomation who is not on the verge of being intubated, consider starting with 1 vial of Anascorp and observe for 30-60 minutes before administering any more. It may reduce the financial hardship of patients and result in significant cost-savings for the hospital, while also reversing venomous effects.

1.
Bronstein A, Spyker D, Cantilena L, Green J, Rumack B, Heard S. 2006 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol (Phila). 2007;45(8):815-917. [PubMed]
2.
Calderón-Aranda E, Dehesa-Davila M, Chavez-Haro A, Possani L. Scorpion stings and their treatment in Mexico. In: Bon C, Goyffon M, eds. Envenomings and Their Treatments. Editions Fondation Marcel Merieux, Lyon; 1996:311-320.
3.
Curry S, Vance M, Ryan P, Kunkel D, Northey W. Envenomation by the scorpion Centruroides sculpturatus. J Toxicol Clin Toxicol. 1983;21(4-5):417-449. [PubMed]
4.
Gateau T, Bloom M, Clark R. Response to specific Centruroides sculpturatus antivenom in 151 cases of scorpion stings. J Toxicol Clin Toxicol. 1994;32(2):165-171. [PubMed]
5.
LoVecchio F, Welch S, Klemens J, Curry S, Thomas R. Incidence of immediate and delayed hypersensitivity to Centruroides antivenom. Ann Emerg Med. 1999;34(5):615-619. [PubMed]
6.
Anascorp [Package Insert]. FDA.gov. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm266725.pdf. Published July 27, 2011.
7.
Boyer L, Degan J, Ruha A, Mallie J, Mangin E, Alagón A. Safety of intravenous equine F(ab’)2: insights following clinical trials involving 1534 recipients of scorpion antivenom. Toxicon. 2013;76:386-393. [PubMed]
8.
Alltucker K. Arizona hospital cuts scorpion antivenom price. USA Today. http://usatoday30.usatoday.com/news/nation/story/2012/09/21/arizona-hospital-cuts-scorpion-antivenom-price/57819892/1. Published September 21, 2012.
9.
Coorg V, Levitan R, Muenzer J, Gerkin R, Ruha A. Clinical Course and Outcomes Associated with Different Treatment Modalities for Pediatric Bark Scorpion Envenomation: 2015 ACMT Annual Scientific Meeting, March 27-29, 2015 Clearwater Beach, FL. J Med Toxicol. 2015;11(1):2-47.
10.
FDA Clinical Review Memorandum – Anascorp. FDA.gov. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm270159.pdf. Published May 6, 2011. Accessed June 6, 2016.
11.
Gonzalez C, Cabral J, Reyes S. Development of an immunoenzymatic assay for the quantification of scorpion venom in plasma. In: Cuernavaca, Mexico; 2000.
12.
Clark R. Antivenom (Scorpion and Spider). In: Goldfrank’s Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill Education; 2010:1582-1586.

Copyedited by Dr. Michelle Lin

Great summary and argument for a more conservative approach to anascorp. I made a few stylistic changes which include:
1. Shortened each paragraph some for readability.
2. I recreated the table on grading/treatment for copyright issues.

Request: Can you reinsert another version of the data table, whereby you save the image as a PDF first and then convert it to a PNG/JPG file? The red squiggly spell-check line is showing up under Anascorp. Alternatively, add the word to your MS Word dictionary so that the underline goes away and re-import this table image.

Michelle Lin, MD
ALiEM Editor in Chief; Professor of Emergency Medicine, UCSF

Expert Peer Review by Dr. Christopher Edwards

Thank you for the invitation to review this interesting article. Full disclosure, I am a believer in 3 vial dosing, as I have had excellent results with this approach and haven\'t been overly impressed with the wait and watch strategy.

There are some fantastic videos demonstrating opsoclonus and tongue fasciculations that are almost pathognomonic for centruroides envenomation that can augment the grading section. I typically use this video for teaching purposes.

Regarding the data evaluating FDA approved dosing vs a more conservative strategy: even if not statistically significant, 0 vs 8.5% rate of admission should be considered clinically significant, particularly if making the argument that the group with fewer admissions (FDA dosing) was sicker at baseline. That being said, the numbers in the conventional dosing group are small enough to make comparisons difficult, but I would be reluctant to change practice based on this alone.

In regards to the dosing originally used in the trial (1 vial): Patients receiving this dosing strategy had a higher incidence of treatment emergent adverse events (TEAEs) compared to higher dosing used later in the study. These TEAEs are not necessarily due to drug toxicity, but could be due to a lack of treatment effect, including events like endotracheal intubation, stridor, and respiratory distress. Dosing was switched to 3 vials mid study as this was the most common total dose administered using the wait and watch approach phase of the study.

My take-away from this would be: \"If you have a patient with a grade III-IV Centruroides envenomation who is not on the verge of being intubated in the next 30 minutes, consider starting with 1 vial of Anascorp and observe for 30-60 minutes before administering any more.\"

Thank you again for the opportunity to get involved with this interesting discussion.

Christopher Edwards, PharmD BCPS
Clinical Assistant Professor, rnThe University of Arizona rnCollege of Pharmacy

Your expertise and in-depth review is much appreciated Dr. Edwards. We have made alterations based on your feedback. While our institution and providers were initially believers in the 3 vial dosing, our colleagues recently completed an evaluation of Anascorp usage over 4 years in our health system (N = 520 patients) comparing patients with Grade III-IV envenomations that received an initial dose of 1 versus 3 vials. There was no significant difference in rate of intubations, admissions, or those receiving one versus three vials in Grade IV cases, although there was a slightly longer LOS in the ED for those starting with 1 vial instead of 3 vials that was significant (0.38 hrs). Patients who started with 1 vial had significantly less Anascorp usage (1.7 vs 3.34 vials, P < 0.001). It should be noted that due to the retrospective nature, provider expertise and patient respiratory condition cannot be evaluated. We look forward to the author publishing their research (Dr. Vanessa Jordan) in the future.

As you mentioned, respiratory compromise should be the limiting factor on whether the 3 vial or 1 vial approach is used and we have tweaked our conclusion to emphasize this.

Michael Sisson, PharmD
Pharmacy Practice Resident Banner; University Medical Center Phoenix
Michael Sisson PharmD

Michael Sisson PharmD

Pharmacist
Chandler Regional Medical Center
Michael Sisson PharmD

Latest posts by Michael Sisson PharmD (see all)

Mark Culver, PharmD, BCPS

Mark Culver, PharmD, BCPS

Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Clinical Instructor - Pharmacy Practice & Science
Mark Culver, PharmD, BCPS
Mark Culver, PharmD, BCPS

Latest posts by Mark Culver, PharmD, BCPS (see all)

  • Great summary and argument for a more conservative approach to anascorp. I made a few stylistic changes which include:
    1. Shortened each paragraph some for readability.
    2. I recreated the table on grading/treatment for copyright issues.

    Request: Can you reinsert another version of the data table, whereby you save the image as a PDF first and then convert it to a PNG/JPG file? The red squiggly spell-check line is showing up under Anascorp. Alternatively, add the word to your MS Word dictionary so that the underline goes away and re-import this table image.

    • Michael Sisson

      Hi Michelle,

      Had to recreate the table to ensure that the Anascorp did not come with that squiggly effect. I’ve updated to the new table (sorry first time using Aliem wordpress). I hope that it’s now up to par. Thank you so much for your time and help. Please let me know if there’s anything else I can do to move forward.

  • Michelle Ruha

    Thanks for this nice summary of scorpion stings and antivenom. Our study, which is described above, is due to be published any day now in the Journal of Medical Toxicology. I have a few comments I would like to add. First – scorpions actually inject venom via a sting (they do not bite, as described in the title). Another important treatment, in my opinion, is opioids. Scorpion stings are extremely painful. I know this to be true, as I was recently stung. Benzodiazepines do nothing to alleviate the pain so I think it is important to provide patients with analgesics in addition to benzodiazepines, which mainly act to control neuromuscular hyperactivity. Also, it is important for emergency physicians to know that respiratory failure can occur as a direct result of the scorpion envenomation, not only due to large doses of benzodiazepines. We recently had a child present with oxygen saturation in the 70s following a scorpion sting prior to ever receiving a dose of medication. As far as the appropriate dosing regimen for treatment of scorpion envenomation…unfortunately I don’t think our study answers the question. The numbers were too small in Group 2 to determine if there were differences in outcome from Group 3, but the hospitalization rate in Group 3 concerns me. Also, I think this study highlights that ‘Grade 4’ is not a great descriptor for severity of illness in scorpion envenomation. A child with a few twitches and some roving eye movements is a Grade 4, as is a child with respiratory failure, severe agitation and violent involuntary jerking and thrashing of limbs. Something I did not state in the publication is that I would continue to recommend an initial 3 vial dose for a young child who presents with a severe Grade 4 scorpion envenomation. I hope in the future we can prospectively study dosing for different severities of envenomation, including for Grade II. The price will need to come down to accomplish that though.

    • Hi Michelle: Thanks for catching the bite vs sting issue. The authors had written “sting” but in my copyediting frenzy, I must have swapped it out for “bite”. I have fixed accordingly. Thanks for catching that.

      • Michelle Ruha

        It’s a common error and I know the authors know the difference! Thank you for the opportunity to share my thoughts regarding the more important issue of management decisions!