Xyla-ed Out: ED Management of Xylazine-associated Skin Wounds
By Harry Lambert
Case
History
DH is a 51-year-old male with a past medical history of bipolar disorder, cocaine and opioid use disorders with associated IV drug use, peripheral artery disorder, and a history of a left femoral artery pseudoaneurysm rupture and subsequent bypass procedure in 2020 who presents to the ED with an acute worsening of his chronic skin wounds, as well as the development of new skin wounds that he’s noticed within the last month. At baseline, the patient has had a chronic skin wound on his right upper extremity for several years but has not had ready access to wound care supplies due to an unstable housing situation. He has sought care at multiple EDs for wound care, which typically results in either short admissions or discharge from the ED. He consistently uses both crack cocaine, which he smokes, and opiates, which he injects, typically into his legs or groin. Recently, he has noticed new and worsening wounds on his legs, which he worries may be caused by exposure to xylazine contamination in his opiate supply. He is presenting to the ED concerned about the progressive enlargement of these wounds and associated pain.
ED Course
Today, he has large open wounds on his right upper extremity and bilateral lower extremities. His wounds are relatively superficial and have visible granulation tissue. There is no visible muscle or bone, nor signs of inflammation such as redness or swelling. Initial labs are notable for anemia, with a hemoglobin of 7.4, no leukocytosis, mild AKI with a BUN/creatinine of 22 and 1.95 respectively, and an elevated CRP to 6.85. His urine toxicology screen is positive for cocaine and opiates, but no other compounds. His extremity x-rays show mild subcutaneous emphysema, but no evidence of osteomyelitis. Given his worsening skin wounds and limited ability to care for them outside the hospital, he is admitted for wound care and further surgical evaluation of his wounds.
Clinical Question: What should ED clinicians consider when treating a patient with possible xylazine-induced wounds?
Background
Xylazine has been used in veterinary medicine for decades as a sedative and analgesic but has not been approved for use in humans (1). The medication causes no known localized toxicity in animals. Although occasional xylazine exposure may have occurred earlier, recurrent cases of xylazine exposure were first noted in the mid-2010s, first in Puerto Rico, then the northeast United States. In recent years, Philadelphia has been found to have the highest incidence of xylazine use; the drug was present in 25.8% of opiate-associated opiate deaths in 2020 (2). Xylazine, often referred to as “tranq,” offers users a deeper, longer lasting high that is desirable, particularly in combination with opiates (2). Traditional ED management strategies for opiate overdoses, such as naloxone, may not be effective in patients with a xylazine-associated overdose. In addition to a different presentation compared to patients who primarily use opiates only, patients with recurrent xylazine usage may present with large, open, nonhealing skin ulcerations. There have been multiple case reports and review articles that focus on the management of acute xylazine toxicity, but few that discuss the management of a patient with chronic wounds that may be secondary to repeated xylazine exposure (3, 4). As xylazine becomes a more common additive in substance mixtures, it is likely that there will be additional patients with xylazine-associated skin wounds.
Figure 1: Xylazine-associated Skin Wound
Pharmacology
Xylazine is an alpha-2 agonist, a close analog of clonidine (see chemical structures in the images below; note the similar structure.) Alpha-2 agonists specifically target the release of dopamine and norepinephrine in the central nervous system, leading to decreased sympathetic activity. Alpha-2 agonists act peripherally as a vasoconstrictor, leading to decreased skin perfusion. Repeated episodes of decreased skin perfusion may lead to skin necrosis and the development of ulcers. This mechanism is theorized to be the underlying cause of the large skin lesions often seen in a patient with repeated xylazine exposure, but the precise pathophysiology is not fully understood (5).
Figure 2, 3: Xylazine (Left), Clonidine (Right)
Current Evidence of Xylazine-Associated Skin Wound Presentation and Treatment
There has been limited systematic study of xylazine-associated skin wounds, but several case studies have been published. Rose et al. write about two cases of xylazine-associated wounds, which were biopsied and found to have “epidermal necrosis with focal fibrin thrombi within superficial small vessels without vasculitis.” (6) Both patients’ wounds resolved with antibiotics and local wound care.
A separate case report from Malayala et al. discussed the treatment of a single patient with opiate use disorder and possible xylazine exposure. Following presentation to the ED, the patient was found to have osteomyelitis in their right tibia, as well as bilateral soft tissue lower extremity abscesses. The patient was admitted, placed on broad-spectrum antibiotics, received bedside wound debridement, and topical wound care. The patient ultimately left against medical advice before treatment completion and represented several times to the emergency department with similar wound-related complaints.
A case series from Wei et al. identified 6 patients with risk factors and likely xylazine-associated skin wounds (8). These patients all developed substantial non-healing skin wounds, which were described as “jagged, angulated ulcers with areas of eschar formation.” (8) Four patients experienced complications including bacteremia, osteomyelitis, and endocarditis (8). Treatments typically included antibiotics and wound care, though two patients required additional surgical debridement. These patients also frequently chose discharge against medical advice, leading to delays and interruptions in their medical treatment and preventing complete wound healing.
A recent NIDA panel on the care of xylazine-adulterated patients discussed the initial evidence and anecdotal experience of Philadelphia health care workers on xylazine-associated wounds (11). The first presenter focused on the outpatient environment, identifying patient stigmatization, malnutrition as a factor in wound healing, wound care supplies access, and rapid decompensation potential as key takeaways (11). The second presenter, a burn surgeon, described the wound quality as “Swiss cheese” in appearance: areas of necrotic eschar interspersed healthy granulation tissue, similar in appearance to vasculitic skin ulcers (11). Given this pathophysiology, she notes that best management has involved limited surgical management, with debridement and grafting often leading to worse outcomes (11). Key reasons to pursue conservative management include the relative likelihood of wound site injection and the challenging outpatient graft-care environment (11). Specifically, she notes that these wounds often heal well with wound-care and cessation of IV drug use (11). Although this is largely anecdotal experience, it further confirms the case reports in the literature and supports a series of recommendations for best management.
Figure 4: Xylazine-Associated Skin wounds typically present with areas of necrotic eschar intermixed with healthy granulation tissue.
Evidence Summary
Although there are only case reports and series to characterize the skin wounds associated with xylazine exposure, several common themes emerge that are summarized here:
1. These patients typically belong to a highly marginalized and stigmatized population that has inconsistent access to medical care. High quality wound care is very difficult in this population.
2. Although xylazine appears to produce skin ulcerations more consistently, these patients are often using multiple substances, some of which may also cause skin ulcerations. For example, cocaine can induce skin ulcers that resemble granulomatosis with polyangiitis (9).
3. The pathogenesis of xylazine-associated skin wounds is still not fully understood but is likely the result of frequent cutaneous arteriole constriction leading to reduced perfusion and associated tissue necrosis.
4. Xylazine-associated skin wounds are typically impressive in size, though they may also present as smaller ulcerations in their early stages. They are consistently characterized by interspersed necrotic eschar and granulation tissue, a property that improves their healing potential.
5. The depth of the wound may vary; osteomyelitis is a concern in patients with these wounds.
6. Treatment is typically centered around infection control and supportive wound care. In roughly half the cases reviewed, the patient required additional surgical debridement.
Recommendations
In general, the ED clinician should maintain a moderate clinical suspicion for deterioration in this patient population. The large wounds, even if not presently infected, may become infected and rapidly progress into sepsis or a necrotizing infection. Despite these large wounds, anecdotal experience suggests that these patients may be classified as sicker than they truly are, given their often visually impressive wounds, and that they may be less likely to decompensate than a patient with a similar size of wound from a different pathology (11).
Specific recommendations to the ED clinician are as follows:
1. Rapport is crucial in this population, as much of chronic wound care occurs outside the hospital. Be mindful that the patient may be suspicious or reluctant to engage with healthcare personnel based on previous experiences.
2. Assess the depth and size of wounds. Consider probing the wound to assess for possible bone involvement.
3. Xylazine-associated skin ulcers are a clinical diagnosis, based on history and risk factors. The ulcers may present similarly to life-threatening diagnoses, including necrotizing fasciitis and gas gangrene.
4. Consider X-Ray vs CT vs MRI for assessment of osteomyelitis. MRI provides the most superior imaging for osteomyelitis (sensitivity 82-100%, specificity 75-96%), but is typically not available in the emergency department. Plain radiographic films typically identify the infection 3-4 weeks after initial onset with a sensitivity of 43-75% and specificity of 75-83%, while CT has a sensitivity of 67% and specificity of 50% (10).
5. There should be a low threshold to send blood cultures in these patients given their risk factors.
6. Broad-spectrum antibiotics should be started only if the patient has clear signs of sepsis, bacteremia, or necrotizing infection.
7. Consider the patient’s nutritional status and whether malnutrition may be contributing to the patient’s ability to heal their wounds.
8. Consider an early surgical consultation to assess for possible debridement, though conservative management may be the best approach for many of these patients, particularly if they are actively still using injectable substances.
9. Admission is desirable in these patients, particularly for an undomiciled patient where a safe environment to perform wound care and maintain wound cleanliness may be a significant concern. The patient may not desire admission, particularly in the setting of limited ability to self-manage their substance use, so the ED clinician should exercise a shared decision-making model and offer multi-modal pain and withdrawal treatment if admission is chosen.
10. If planning for discharge, the ED clinician should closely assess the patient’s wound care supply access. Social work should be involved early to help with disposition planning, but the clinician should strongly consider sending the patient with additional wound care supplies.
References
1. Greene SA, Thurmon JC. Xylazine--a review of its pharmacology and use in veterinary medicine. J Vet Pharmacol Ther. 1988 Dec;11(4):295-313. doi: 10.1111/j.1365-2885.1988.tb00189.x. PMID: 3062194.
2. Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend. 2022 Apr 1;233:109380. doi: 10.1016/j.drugalcdep.2022.109380. Epub 2022 Feb 26. PMID: 35247724; PMCID: PMC9128597.
3. Love JS, et al. Opioid overdoses involving xylazine in emergency department patients: a multicenter study. Clin Toxicol (Phila). 2023 Mar;61(3):173-180.
4. Gupta R: Xylazine – Medical and public health imperatives. N Engl J Med. 2023; 15;388(24):2209-2212.
5. Bishnoi A, Singh V, Khanna U, Vinay K. Skin ulcerations caused by xylazine: A lesser-known entity. J Am Acad Dermatol. 2023 Aug;89(2):e99-e102. doi: 10.1016/j.jaad.2023.04.009. Epub 2023 Apr 11. PMID: 37054812.
6. Rose L, Kirven R, Tyler K, Chung C, Korman AM. Xylazine-induced acute skin necrosis in two patients who inject fentanyl. JAAD Case Rep. 2023 Apr 26;36:113-115. doi: 10.1016/j.jdcr.2023.04.010. PMID: 37288443; PMCID: PMC10242481.
7. Malayala SV, Papudesi BN, Bobb R, Wimbush A. Xylazine-Induced Skin Ulcers in a Person Who Injects Drugs in Philadelphia, Pennsylvania, USA. Cureus. 2022 Aug 19;14(8):e28160. doi: 10.7759/cureus.28160. PMID: 36148197; PMCID: PMC9482722.
8. Wei J, Wachuku C, Berk-Krauss J, Steele KT, Rosenbach M, Messenger E. Severe cutaneous ulcerations secondary to xylazine (tranq): A case series. JAAD Case Rep. 2023 Apr 26;36:89-91. doi: 10.1016/j.jdcr.2023.04.016. PMID: 37274146; PMCID: PMC10232457.
9. FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugs Date accessed: March 22, 2023
10. Pineda C, Espinosa R, Pena A. Radiographic imaging in osteomyelitis: the role of plain radiography, computed tomography, ultrasonography, magnetic resonance imaging, and scintigraphy. Semin Plast Surg. 2009 May;23(2):80-9. doi: 10.1055/s-0029-1214160. PMID: 20567730; PMCID: PMC2884903.
11. Harroz, R, Perrone, J, Klipp, S, Rae, L. Patients Taking Xylazine-Adulterated Opioids in Emergency, Hospital, & Addiction Care Settings. National Institute on Drug Abuse webinar. August 1, 2023. Accessed September 2, 2023. https://www.youtube.com/watch?v=DG8zPpkrv64&t=5338s
Image Sources
1. Wei J, Wachuku C, Berk-Krauss J, Steele KT, Rosenbach M, Messenger E. Severe cutaneous ulcerations secondary to xylazine (tranq): A case series. JAAD Case Rep. 2023 Apr 26;36:89-91. doi: 10.1016/j.jdcr.2023.04.016. PMID: 37274146; PMCID: PMC10232457.
2. https://pubchem.ncbi.nlm.nih.gov/compound/Xylazine
4. Malayala SV, Papudesi BN, Bobb R, Wimbush A. Xylazine-Induced Skin Ulcers in a Person Who Injects Drugs in Philadelphia, Pennsylvania, USA. Cureus. 2022 Aug 19;14(8):e28160. doi: 10.7759/cureus.28160. PMID: 36148197; PMCID: PMC9482722.
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