CASE STUDY The Treatment of Black Widow Spider Envenomation with Antivenin Mactans: A Case Series

Steven R Offerman, MD, FACEP, FACMT G Patrick Daubert, MD, FACEP Richard F Clark, MD, FACEP, FACMT hourglass pattern (red or orange Abstract in color) on the ventral aspect of Black widow spiders () are found throughout the their shiny, black abdomen (Figure US. Though bites are relatively uncommon, they pose a significant health 1). Male widow spiders are much problem with over 2500 reported to American control centers smaller and lighter in color, and annually. Black widow spider bites cause a characteristic envenomation they lack the ability to deliver syndrome consisting of severe pain, muscle cramping, abdominal pain, . Black widow spiders are and back pain. The significant pain associated with envenomation is often commonly found in garages, trash refractory to traditional analgesics. (Antivenin Latrodectus mac- heaps, and outbuildings but are tans) is available and effective, but is often withheld because of a fear of uncommon in occupied dwell- acute hypersensitivity reactions. We report four cases of symptomatic black ings. Bites are usually defensive, widow spider envenomation. One of the reported cases was managed occurring when the spider is ac- without antivenom, and, in contrast, three were treated successfully with cidentally disturbed.4 Antivenin Latrodectus mactans. We believe that these cases demonstrate Black widow spider envenom- safe and effective use of black widow antivenom. This article presents the ation remains a significant health rationale for use of antivenom in these cases, and a nonsystematic review problem in the US, being reported of the pertinent literature. over 2500 times annually to US poison-control centers.1,2 The ac- Background (L mactans), the northern black tual number of envenomations is Latrodectus species are found widow (L variolus), the Western probably much higher, because throughout the world. Five spe- black widow (L hesperus), the poison-center estimates tend to cies of widow spiders occur in brown widow (L geometricus), underreport exposures.6 Black the US: the southern black widow and the red widow (L bishopi). In widow spider envenomation fre- North America, the most widely quently results in severe pain, distributed native spider is L mac- muscle cramps, abdominal pain, tans, known as the black widow back pain, and hypertension. These spider.1,2 Although most spiders symptoms may be refractory to produce venom, the vast major- traditional therapies. However, ity lack mouthpieces (chelicerae) envenomation is associated with capable of delivering their venom low mortality.4,7 Only three cases through human skin.3–5 Black wid- of deaths associated with widow ow spiders are one of only a few spiders have been reported in the spiders with the ability to cause a world medical literature. Two were poisonous bite to humans.3,4 Only patients from Madagascar bitten by

Photo by G Patrick Daubert, MD. female widow spiders are danger- L geometricus species, and the third Figure 1. Female black widow spider. ous. They can be identified by the was a young Greek woman who

Steven R Offerman, MD, FACEP, FACMT, is the Co-Director of the Kaiser Permanente Northern California Regional Service and Assistant Chief of the Department of Emergency Medicine for the Kaiser Permanente South Sacramento Medical Center in CA. E-mail: [email protected]. G Patrick Daubert, MD, FACEP, is the Co-Director of the Kaiser Permanente Northern California Regional Toxicology Service, Department of Emergency Medicine for the Kaiser Permanente South Sacramento Medical Center in CA. E-mail: [email protected]. Richard F Clark, MD, FACEP, FACMT, is the Director of the Division of Medical Toxicology in the Department of Emergency Medicine at the University of California San Diego Medical Center in CA. E-mail: [email protected].

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died of after being bitten ED, which did not provide relief. appeared uncomfortable and was by an L tredecimguttatus spider.8,9 Because of concern about a hy- treated with intravenous diaz- There are no known cases of death persensitivity reaction, he was not epam and ketorolac, which did resulting from envenomation by the given Antivenin Latrodectus mac- not provide relief. During his ED widow species found in the US. tans. He was eventually admitted stay, his pain became more severe, Antivenin Latrodectus mactans to the pediatric ward for further requiring multiple doses of hydro- (Merck & Co, Inc, Whitehouse pain control. In the hospital, he morphone for control. The patient Station, NJ) is the only antivenom received ketorolac every 6 hours stood bent over the gurney and currently available in the US for and hydromorphone every 4 hours appearing very uncomfortable. treatment of black widow spider en- for 2 days. A consultation with the His lungs were clear, and findings venomation.10 Despite the significant Medical Toxicology Service was on his cardiac and abdominal ex- symptoms that may develop after not obtained. On the third hospital aminations were normal. His left envenomation, the use of antivenom day, the boy began to feel better middle toe showed no discernible is a subject of debate within the and was discharged to his home bite marks, swelling, or erythema. toxicology community. This contro- that afternoon. After discharge, his Because of the patient’s severe versy stems primarily from a single symptoms resolved completely, pain, the medical toxicologist reported case of fatal hypersensitivity and he had experienced no fur- thought that Latrodectus antivenom related to spider antivenom admin- ther sequelae when evaluated 6 would be appropriate for treat- istration. We describe here one case months later. ment. The benefits and risks of in which envenomation was treated treatment were discussed, and then without antivenom and three cases Case 2 the patient stated, “I would rather in which Antivenin Latrodectus mac- A previously healthy man, age die taking the medicine than feel tans was used safely and effectively. 35 years, arrived in the ED ap- the pain the way I do.” One vial of proximately 1 hour after sustaining Antivenin Latrodectus mactans (2.5 Case Presentations a bite to his left middle toe from mL) was infused intravenously dur- Case 1 what he described as a “black ing a 30-minute period. Within 15 A previously healthy boy, age spider.” He was doing yard work, minutes of infusion completion, he 3 years, arrived in the Emergency wearing boots that were “open at began experiencing relief. No fur- Department (ED) 1.5 hours after the top,” when he felt a sudden ther hydromorphone was required. suffering a black widow pain in his toe. When he removed He was observed in the ED for 2 to the top of his right foot while the boot to investigate, a black hours and then discharged to his putting on his boots. The parents spider ran out. Within 5 minutes home. A follow-up appointment brought the spider to the ED, where of the incident, he began feeling was scheduled for 48 hours later, it was identified as a female black severe pain, cramping, and par- but he did not keep it. A review widow. There was a 2-by-2-cm area esthesias in his left leg. The pain of the medical records showed of mild erythema to the top of the progressed to include his abdo- no return visits to the ED and no boy’s foot. Over the next hour, the men, low back, and chest. In the further clinic visits by the patient. boy developed severe foot, leg, ED, the patient complained that He was not available for long-term groin, and abdominal pain. His the pain was so severe that it was follow-up assessment. vital signs were as follows: blood difficult to sit or lie down. Because pressure, 111/68 mmHg; respiratory the patient’s description of the Case 3 rate, 20 to 30 breaths/min; heart spider that bit him and the classic A woman, age 24 years, arrived rate, 103 beats/min; temperature, clinical syndrome, his symptoms in the ED and said that she had 98.4°F; pulse oxygen saturation, were believed to be caused by sustained a black widow spider 99% on room air. His lungs were Latrodectus envenomation. bite on her right shoulder. The clear, and findings on his cardiac His vital signs were as follows: spider was on a shirt that she put and abdominal examinations were blood pressure, 146/72 mmHg; on. The patient had mild erythema normal. He cried constantly and respiratory rate, 18 breaths/min; without swelling at the bite site. complained of severe pain. heart rate, 71 beats/min; tem- She complained of severe pain The patient was treated with perature, 97.8°F; pulse oxygen and muscle cramps in the shoulder, and lorazepam in the saturation, 99% on room air. He neck, and back. Her vital signs

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were as follows: blood pressure, in a shoe that the boy put on. The One patient was treated without 143/94 mmHg; respiratory rate, mother had brought the spider to antivenom, and the other three pa- 18 breaths/min; heart rate, 101 the ED, and it was clearly identifi- tients were successfully and safely beats/min; temperature, 97.8°F; able as a female black widow. The treated with Antivenin Latrodectus pulse oxygen saturation, 99% on patient complained of severe pain mactans. We believe that the rapid room air. She appeared extremely that began in his foot and then symptomatic improvement and uncomfortable. Her lungs were progressed to his leg, low back, favorable outcomes we observed clear, and findings on her cardiac abdomen, and chest. in these cases were directly at- and abdominal examinations were At presentation, his vital signs tributable to the use of spider normal. She was treated with were as follows: blood pressure, antivenom. Antivenom provides hydromorphone, ketorolac, meto- 134/92 mmHg; respiratory rate, 26 rapid pain relief and may help to clopramide, and lorazepam, which breaths/min; heart rate, 96 beats/ avoid hospital admissions and/or provided minimal relief. min; temperature, 97.8°F; pulse oxy- repeat ED visits. Latrodectus antivenom therapy gen saturation, 96% on room air. He Latrodectus venom is one of the was recommended by the medical appeared to be in distress. He was most potent by volume, toxicologist because of her severe diaphoretic. His abdomen was tight, containing at least five insecticidal pain. After intravenous infusion of and he exhibited diffuse guarding. , a -specific neuro- a single vial (2.5 mL) of Antivenin His lungs were clear, and findings on (α-), and one toxin Latrodectus mactans, the patient his cardiac examination were normal. affecting crustaceans. The primary experienced significant relief and There was mild erythema of his right toxin responsible for the enven- required no further pain medica- second toe, but there were no iden- omation syndrome in humans is tion. She was discharged to her tifiable puncture marks. While in the α-latrotoxin. The neurotoxin binds home after 2.5 hours of observation. ED, the patient began to complain of to specific presynaptic receptors She did not return to the ED or to difficulty breathing. He was treated (neurexin 1a and CIRL) that pre- her primary physician for further with morphine and diazepam, which cipitate release, treatment. At a follow-up evaluation did not provide relief. particularly and more than 1 year after the incident, Latrodectus antivenom was rec- .4 Release of these she reported having no further se- ommended by the on-call toxicolo- is responsible quelae after leaving the ED and no gist for treatment of his severe pain. for the classic envenomation syn- symptoms of serum sickness. A single vial (2.5 mL) of Antivenin drome seen with these bites. Latrodectus mactans was infused Black widow spider bites oc- Case 4 intravenously during a 20-minute cur most commonly to the lower A boy, age 8 years, was brought period. During infusion, he began extremities, followed by the upper to the ED by his mother approxi- experiencing relief of his symptoms. extremities and then the trunk.3,11,12 mately 3 hours after sustaining Within 20 minutes, he was feeling Interestingly, reports of early series a black widow spider bite to his better and described his pain as noted higher numbers of bites to right second toe. The spider was being at a level of 1 on a scale of 1 the trunk (ie, the buttocks and to 10. After 1.5 hours of observation genitalia) related to outhouse ex- in the ED, he was released to his posures.13 No association between home. He was seen for a follow-up bite location and envenomation evaluation 2 days later and reported severity has been found.7 Local no further pain and had required no bite site findings are variable, in- oral pain . At a follow-up cluding tiny puncture marks, mild evaluation more than 1 year later, he erythema, and an erythematous reported no further sequelae and no target-like lesion11,14 (Figure 2). symptoms of serum sickness. Symptoms of envenomation in- clude diaphoresis, hypertension, Discussion muscle cramping, weakness, and Provided by Richard F Clark, MD. Figure 2. Example of local appearance of Latrodec- Of the four cases discussed pain either near or distant from tus mactans bite to the neck. (This photograph is here, three involved bites to the the site of envenomation. The most not from any of the presented cases.) feet and one to the right shoulder. common presenting symptoms are

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Table 1. Signs and symptoms ered to be an antidote for black dectus mactans administration. 17 of black widow spider widow envenomation. Calcium Although these reactions do oc- envenomation2,4,7,11,15,27-29 was thought to stabilize nerve cur, relatively few minor reactions 3,6,14 Local pain at envenomation site membrane permeability, result- have been reported, and only Local diaphoresis of envenomation ing in decreased neurotransmitter one report of a severe reaction can site and/or extremity release.16,17 Although this effect be found in the medical literature.3 Muscle pain in envenomated was demonstrated in vitro and Unfortunately, that one case is extremity reported in some early clinical frequently cited as the reason to Generalized muscle pains in series,13,16-18 subsequent experi- avoid administering antivenom back, abdomen, and/or chest (may 3,6 mimic “”—severe ence has not shown effectiveness. to symptomatic patients. Crit- abdominal pain of acute onset Therefore, calcium therapy has ics believe that because black and of unknown cause) lost favor in the medical toxicol- widow spider envenomation is Diaphoresis remote from ogy community.3–6 generally a nonfatal condition, it is envenomation site The only therapies with proven too risky to administer such treat- Facies latrodectismica (painful effectiveness are opioid anal- ment with even a single reported grimace, flushing, diaphoresis, trismus, blepharitis) gesics and black widow spider fatality reported in the medical Abnormal vital signs (tachypnea, antivenom. Antivenin Latrodectus literature. The case at the heart of tachycardia, and/or hypertension) mactans is an equine-derived anti- controversy, however, involved Shortness of breath venom based on immunoglobulin a young woman with history of Nausea and G.4,10,19,20 The proposed pharma- asthma and multiple medication Headache cologic mechanism is binding of allergies who received a rapid, Priapism (rare) venom toxic constituents by the undiluted bolus of antivenom. Myocarditis (rare) antivenom antibodies. A single She had a severe hypersensitiv- vial (2.5 mL) generally provides ity reaction. Unfortunately, her abdominal and/or back pain that adequate relief in human (adult or resuscitation was complicated by may be very severe and difficult to pediatric) cases.3-5,14,19,21 a pneumothorax and a protracted treat (Table 1). Severe abdominal The Kaiser Permanente (KP) hospital stay, and she eventually pain mimicking “acute abdomen” acquisition cost for one vial of died.2,3,6 Although that case was has even been reported.15 Although Antivenin Latrodectus mactans tragic, we do not believe that it these symptoms can be extremely was $27.71 in 2011. In the largest represents sufficient evidence for uncomfortable, permanent disabil- series reported to date of moder- abandoning antivenom use on the ity and death are rare.4,7 Treatment ate to severe black widow spider grounds that it is unsafe. The cur- of black widow spider envenom- envenomation (n = 163), patients rent package insert for Antivenin ation can be challenging, often treated with antivenom experi- Latrodectus mactans calls for infu- necessitating large doses of pain enced a much shorter duration of sion of diluted antivenom during medication and/or hospital admis- symptoms and were less likely to a period of 15 to 30 minutes.10 At sion. In one study, 52% (39 of 76) be admitted to the hospital than these slower infusion rates, im- of patients with black widow bites those who did not receive antiven- mediate hypersensitivity appears who did not receive antivenom om.3 Relief of symptoms occurred to be extremely rare.6 required hospital admission for within an average of 31 minutes We believe that antivenom, further treatment.3 of antivenom infusion.3 Adminis- when given correctly, is safe and The traditional therapies for tration of antivenom even late in should be considered in cases black widow spider envenomation the course of envenomation has of envenomation with systemic are aimed at providing symptom- been reported to be effective.21,22 symptoms or severe local symp- atic relief while venom effects In one reported case, antivenom toms. Though it is not mentioned resolve. These include primarily was used effectively for the treat- on the package insert for An- opioid analgesics and muscle re- ment of symptoms 90 hours after tivenin Latrodectus mactans, laxants. Past trials involving these a black widow spider bite.22 patients may be pretreated with therapies have shown partial Acute hypersensitivity reactions diphenhydramine and/or steroids success at best.3,4,6,16 In addition, are the most feared complication in an attempt to blunt a hyper- calcium therapy was once consid- associated with Antivenin Latro- sensitivity response.5,6 Multiple

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allergies, asthma, or past reactions selti [CSL Limited, Parkville, Victoria, sis and management of the critically to equine-based products should Australia]), the incidence of serum poisoned patient. Philadelphia, PA: be considered contraindications.10 sickness was 1.7%.11 Elsevier Mosby; 2005. p 1187–93. 3. Clark RF, Wethern-Kestner S, Vance Black widow spider enven- Antivenin Latrodectus mactans MV, Gerkin R. Clinical presenta- omation in pregnancy has been has been used for more than 70 tion and treatment of black widow recommended as an indication for years. A new Fab antibody-based spider envenomation: a review of antivenom because of the risk of antivenom is currently in develop- 163 cases. Ann Emerg Med 1992 venom-induced abortion or other ment and in phase 3 trials. The Jul;21(7):782–7. possible harm to the fetus4,23; how- hope is that this product will be 4. Hahn IH, Lewin NA. . In: Flomenbaum NE, Goldfrank L, ever, the actual risk is not equally effective but carry a lower Hoffman R, Howland MA, Lewin known. In one report of a risk of hypersensitivity reactions. N, Nelson L. Goldfrank’s toxicologic … antivenom, poison-center study of 97 KP Northern California has a re- emergencies. 8th ed. New York: when given black widow spider bites gional on-call Medical Toxicology McGraw-Hill Professional; 2006. p correctly, 1603–22. in pregnant females, there consultation service offering assis- is safe and 5. Peterson ME. Black widow spider were no miscarriages.24 tance in treating poisoned patients. should be envenomation. Clin Tech Small Anim Although Antivenin Lat- considered Pract 2006 Nov;21(4):187–90. rodectus mactans is a cat- Conclusion 6. Clark RF. The safety and efficacy of in cases of egory C drug, it has been In three of four cases of symp- antivenin Latrodectus mactans. J envenomation given in pregnancy with- tomatic black widow spider en- Toxicol Clin Toxicol 2001;39(2):125–7. with systemic out consequence.25,26 Even venomation, we administered 7. Moss HS, Binder LS. A retrospective symptoms or review of black widow spider en- though absolute safety is Antivenin Latrodectus mactans severe local venomation. Ann Emerg Med 1987 impossible to prove, there and observed rapid and complete symptoms. Feb;16(2):188–92. is nothing currently to sug- resolution of symptoms. These 8. Ramialiharisoa A, de Haro L, Jouglard gest that spider antivenom cases demonstrate the safe and J, Goyffon M. [Latrodectism in Mada- is unsafe in pregnancy. Antivenin effective use of spider antivenom. gascar]. [Article in French]. Med Trop Latrodectus mactans does contain Our review of the literature sug- (Mars) 1994;54(2):127–30. 9. Pneumatikos IA, Galiatsou E, Goe D, the preservative thimerosal, but gests that the witnessed effects Kitsakos A, Nakos G, Vougiouklakis the amount of mercury associated of antivenom are usual, which TG. Acute fatal toxic myocarditis with an antivenom dose would not leads us to believe that Antivenin after black widow spider enven- be expected to cause fetal harm.24 Latrodectus mactans is safe when omation. Ann Emerg Med 2003 The package insert for Antivenin given correctly. v Jan;41(1):158. Latrodectus mactans does warn of 10. Antivenin Latrodectus mactans [package insert]. Whitehouse Station, the potential for (delayed) serum Disclosure Statement NJ: Merck & Co, Inc; 2005. sickness after antivenom adminis- This study received no funding. The 11. Sutherland SK, Trinca JC. Survey tration. In contrast to equine-based author(s) have no conflicts of interest to of 2144 cases of red-back spider snake antivenom (Antivenin Crotali- disclose. bites: Australia and New Zealand, dae Polyvalent [Wyeth-Ayerst, West 1963–1976. Med J Aust 1978 Dec Acknowledgment 30;2(14):620–3. Greenwich, RI]), which required Katharine O’Moore-Klopf, ELS, of KOK 12. Isbister GK, Gray MR. Latrodectism: much larger doses and was associ- Edit provided editorial assistance. a prospective cohort study of bites ated with serum sickness in the by formally identified redback majority of patients, Latrodectus an- References spiders. Med J Aust 2003 Jul tivenom usually requires only a single 1. Bronstein AC, Spyker DA, Cantilena 21;179(2):88–91. vial, and there are few reports of LR Jr, Green JL, Rumack BH, Giffin 13. Kirby-Smith HT. Black widow 5,6,14 SL. 2008 Annual report of the spider bite. Ann Surg 1942 serum sickness from it. Although American Association of Poison Feb;115(2):249–57. the exact rate of serum sickness after Control Centers’ National Poison 14. Nordt SP, Lee A, Sasaki K, Clark RF, black widow spider antivenom is Data System (NPDS): 26th annual Cantrell FL. Retrospective review unknown, our review of the literature report. Clin Toxicol (Phila) 2009 of black widow spider antive- leads us to believe that it is low. In Dec;47(10):911–1084. nom use [abstract 110]. Clin Toxicol 2. Daly FFS, White J. Widow and related one study of Australian red-back spi- 2010;48(6):627. Available from: Latrodectus spiders. In: Brent J, Wal- www.eapcct.org/publicfile.php?folder der antivenom (a similar antivenom lace K, Burkhart K, Phillips S, Donovan =congress&file=Abstracts_Denver.pdf. product, Antivenin Latrodectus has- J, eds. Critical care toxicology: diagno- 15. Bush SP. Black widow spider enven-

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omation mimicking cholecystitis. Am 20. Heard K, O’Malley GF, Dart RC. (Latrodectus mactans) envenomation J Emerg Med 1999 May;17(3):315. Antivenom therapy in the Americas. in a term pregnancy. Curr Surg 2000 16. Key GF. A comparison of calcium Drugs 1999 Jul;58(1):5–15. Jul 1;57(4):346–8. gluconate and methocarbamol 21. Suntorntham S, Roberts JR, Nilsen 27. Handel CC, Izquierdo LA, Curet LB. (Robaxin) in the treatment of GJ. Dramatic clinical response to Black widow spider (Latrodectus Latrodectism (black widow spider the delayed administration of black mactans) bite during pregnancy. envenomation). Am J Trop Med Hyg widow spider antivenin. Ann Emerg West J Med 1994 Mar;160(3):261–2. 1981 Jan;30(1):273–7. Med 1994 Dec;24(6):1198–9. 28. Quan D, Ruha AM. Priapism as- 17. Gilbert EW, Stewart CM. Effective 22. O’Malley GF, Dart RC, Kuffner EF. sociated with Latrodectus mactans treatment of arachnidism by calcium Successful treatment of latrodectism envenomation. Am J Emerg Med salts: a preliminary report. Am J Med with antivenin after 90 hours. N Engl 2009 Jul;27(6):759.e1–2. Sci 1935;189(4):532–6. J Med 1999 Feb 25;340(8):657. 29. Sari I, Zengin S, Davutoglu V, Yildirim 18. Timms PK, Gibbons RB. Latro- 23. Russell FE, Marcus P, Streng JA. Black C, Gunay N. Myocarditis after black dectism—effects of the black widow spider envenomation during widow spider envenomation. Am widow spider bite. West J Med 1986 pregnancy. Report of a case. Toxicon J Emerg Med 2008 Jun;26(5):630. Mar;144(3):315–7. 1979;17(2):188–9. e1–3. 19. Bronstein NA. Antidotes in depth: an- 25. Wolfe MD, Meyers O, Carvati EM, 30. Hoover NG, Fortenberry JD. Use of tivenom ( and spider). In: Flo- Rayburn WF, Seifert SA. Black widow antivenin to treat priapism after a menbaum NE, Goldfrank L, Hoffman spider envenomation in pregnancy. black widow spider bite. Pediatrics R, Howland MA, Lewin N, Nelson J Matern Fetal Neonatal Med 2011 2004 Jul;114(1):e128–9. L. Goldfrank’s toxicologic emergen- Jan;24(1):122–6. cies. 8th ed. New York: McGraw-Hill 26. Sherman RP, Groll JM, Gonzalez Professional; 2006. p 1623–8. DI, Aerts MA. Black widow spider

A Timid Little Beastie Consider the black widow spider. It’s a timid little beastie, useful and, for my taste, the prettiest of the arachnids, with its shiny, patent-leather finish and its red hourglass trademark. But the poor thing has the fatal misfortune of possessing enormously too much power for its size. So everybody kills it on sight. — Stranger in a Strange Land. Robert A Heinlein, 1907-1988, American science fiction author

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