Opioid‐related xylazine toxicity manifesting as myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema

Abstract

This article provides a report of a case of organ dysfunction, myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema after a patient's use of xylazine and fentanyl. Within the US opioid epidemic, xylazine is emerging as a troubling national sub‐story. The prevalence of xylazine within illicitly manufactured opioids and the proportion of opioid‐involved overdose deaths with detected xylazine are rising dramatically, the latter increasing 276% between 2019 and 2022. A 27‐year‐old woman with opioid use disorder, active intravenous drug use, and prior bacteremia presented to our institution's emergency department (ED) with left lower extremity pain and associated weakness, new acute bilateral hearing loss, multiple electrolyte derangements, and cerebral infarcts followed by cerebral edema, leading to an emergent sub‐occipital decompressive craniectomy and placement of an external ventricular drain. A definitive mechanism was not determined; however, we hypothesized that xylazine toxicity played a role in her clinical presentation, which could have future clinical implications, including the possibility to incorporate xylazine as part of toxicology screens.

1. INTRODUCTION

Xylazine, colloquially known as “tranq” and “zombie drug”, is a non‐opioid alpha‐2‐agonist, like clonidine, that is progressively being found nationally in the illicit drug market. It can cause skin necrosis, tissue injury, and poor wound healing. ¹ It was originally studied as an antihypertensive drug in humans, but due to its sedative effects, it was never approved by the FDA for human use. ² The drug is currently used in veterinary medicine for sedation in horses, dogs, and cattle, among other species. ³ However, it is now found in the illicit human drug supply in combination with heroin and fentanyl. In 2023, the Office of National Drug Control Policy designated fentanyl with xylazine as an emerging threat nationally. ⁴ In Philadelphia, where this case occurred, xylazine is found in 31% of heroin and fentanyl overdose deaths. ²

2. CASE REPORT

A 27‐year‐old woman with opioid use disorder, active intravenous drug use, and prior bacteremia presented to our institution's emergency department (ED) with left lower extremity pain and associated weakness, new acute bilateral hearing loss, and multiple electrolyte derangements. She was asymptomatic the night prior and awoke with new deafness and lower extremity symptoms, which prompted her to seek care. She affirmed only to intravenous heroin use the prior week, which she had injected into a blood vessel in her neck.

On presentation, the patient was tachycardic to 100–110 beats per minute, normotensive, and afebrile with a respiratory rate of 14 breaths per minute. She was encephalopathic and had left leg and left groin pain with normal muscle bulk but inability to move the leg against gravity, with range of motion limited by pain, and decreased sensation in left lower extremities. There were no skin changes to the left groin and no tense compartments. Skin was notable for diffuse erythematous papules on bilateral extremities without fluctuance and warmth.

Laboratory studies were notable for an acute kidney injury (AKI) (creatinine 2.13 mg/dL), liver injury (aspartate aminotransferase 1443 U/L, alanine aminotransferase 521 U/L), hyperkalemia (7.3 mmol/L), leukocytosis (35.3 × 10³//μL), hyponatremia (128 mmol/L), elevated creatine kinase (117, 000 U/L), positive pregnancy test (beta‐human chorionic gonadotropin 825 mIU/mL), and metabolic and respiratory academia with elevated lactate (pH 7.16, PCO₂ 48 mmHg, lactate 6.3 mmol/L). Computed tomography (CT) scan of the head showed hypodensities in bilateral cerebellar hemispheres and left basal ganglia, which were initially concerning for embolic infarcts involving multiple vascular territories. The patient was admitted from the ED to the medical intensive care unit for presumed septic shock due to high‐grade bacteremia with concern for infective endocarditis or skin and soft tissue infection with necrotizing fasciitis or abscess. Her initial management included 4 L of intravenous crystalloid fluid, insulin, D50, calcium gluconate, bicarbonate, vancomycin, piperacillin‐tazobactam, and morphine.

On hospital day 2, CT scan of the chest, abdomen, and pelvis did not reveal any ischemic infarcts or acute abnormalities. CT scan of the left lower extremity demonstrated myositis of the medial proximal thigh muscles with concern for myonecrosis complicated by severe rhabdomyolysis. Repeat creatine kinase was 149,000 U/L; however, on physical examination, her thigh compartments remained soft, and no immediate fascial decompression was required. Additionally, doppler ultrasound of bilateral lower extremities did not reveal any venous thrombus. Vancomycin was changed to linezolid, and she was continued on piperacillin‐tazobactam. Urine drug screen returned positive for fentanyl, xylazine, benzodiazepine (which was prescribed), and tetrahydrocannabinol. A pelvic ultrasound was completed to follow up her positive pregnancy test; however, there was no intrauterine gestation seen on pelvic ultrasound, suggesting an intrauterine gestation that was too early to visualize, a spontaneous abortion, or an ectopic pregnancy. On hospital day 3, the patient had global clinical improvement including in her hearing loss, encephalopathy, AKI, rhabdomyolysis, and leg weakness, although her leg pain remained. Transthoracic echocardiogram did not reveal any valvular vegetations, and multiple blood cultures remained sterile throughout her admission, thus decreasing the probability of infective endocarditis.

The patient was transferred to the medical floor on day 4. She experienced spontaneous expulsion of products of conception from her pregnancy consistent with a spontaneous abortion. Magnetic resonance imaging (MRI) of the brain was completed to characterize the hypodensities initially visualized on her CT scan. This study showed diffusion restricting signal abnormalities, predominantly within the bilateral cerebellar hemispheres and bilateral globi pallidi with associated mass effect and interval enlargement of the supratentorial ventricles, concerning for development of early hydrocephalus. Neurosurgical intervention was initially deferred, given the patient's reassuring neurological examination and appropriate mentation, but she was transferred to the neurological intensive care unit for close monitoring. In the evening of day 4, the patient developed a headache, lethargy, and bradycardia. Emergent repeat CT scan of the head showed worsening posterior fossa edema with increased ventricular size consistent with acute hydrocephalus with mass effect and impending herniation. On day 5, the patient had an emergent sub‐occipital decompressive craniectomy and placement of an external ventricular drain (EVD) and was started on hypertonic saline. Her neurological examination showed swift improvement post‐decompression. MRI head on day 15 showed bilateral globus pallidus and cerebellar hemisphere cytotoxic edema, with the EVD appropriately placed. Her course was further complicated by EVD clotting requiring revision and intraventricular hemorrhage and tract hemorrhage. Her hydrocephalus resolved, the EVD was removed, and she was discharged to a rehabilitation facility on hospital day 34 with minor sensorimotor deficits of her left lower extremity and an otherwise normal neurological exam.

3. DISCUSSION

Xylazine, a non‐opioid alpha‐2‐agonist, inhibits the release of noradrenaline through the brain. ⁵ In animals, the cardiovascular response to xylazine is biphasic. Initially, blood pressure and systemic vascular resistance increase due to direct action on vasoconstriction‐mediating alpha‐1 and 2‐adrenoceptors, whereas heart rate and hence cardiac output decrease because of baroreceptor activation. ⁶ This is followed by a second phase marked by decrease in arterial pressure and heart rate and cardiac output remain lower than normal resulting from decreased sympathetic nervous activity. ⁷

In humans, if administered intravenously, there is a transient increase in arterial blood pressure and myocardial contraction secondary to vagal nerve stimulation, followed by sustained hypotension, bradycardia, and decreased myocardial contractility. ⁸ Unlike in animals, in humans, xylazine causes respiratory depression, which can lead to patients needing ventilatory assistance. ⁹ , ¹⁰ Many of its pharmacological effects are like those of heroin and fentanyl, and the two classes can have synergistic effects when used concomitantly. ¹¹ Atipamezole, an alpha‐2‐antagonist, which is approved for use in animals, is the preferred reversal agent. ¹² In the absence of an approved reversal agent, treatment of xylazine toxicity in humans includes supportive care with naloxone use to target the opioid in which xylazine is often mixed.

This patient presented with symptoms for which xylazine toxicity, both systemically and locally, could support the diagnosis, as xylazine was confirmed by urine drug screen. The patient arrived normotensive and tachycardic with new onset hearing loss, multifocal hypodensities in the cerebellum and basal ganglia on initial CT scan, and left lower extremity pain. Through the systemic uptake of xylazine, there was likely a transient increase in arterial blood pressure due to microvascular constriction. This may have led to the patient presenting as normotensive and having symptoms of small‐vessel ischemia in disparate tissue beds, including in auditory conduction or processing areas, though MRI brain near the end of admission did not reveal pons infarct to explain the transient hearing loss. Notably, opioids have also been found to cause transient deafness. ¹³ The diffuse small vessel ischemia may have contributed to the spontaneous abortion, as vascular constriction has been found to be associated with pregnancy loss; the spontaneous abortion may have also been unrelated or due to other stressors. ¹⁴

Xylazine may also be causative of the soft tissue necrosis in her leg through decreased blood flow, leading to myonecrosis and an associated elevated creatine kinase. ¹⁵ Xylazine is known to cause necrotic wounds that do not always correlate at the sight of injection. ¹ This may explain the skin lesions on the patient's extremities. Finally, the patient had a mixed respiratory and metabolic acidosis. This may reflect both primary xylazine‐induced respiratory acidosis and a metabolic acidosis from xylazine‐related distal tissue injury leading to AKI and elevated lactate.

Improvement of the patient's bilateral hearing loss may reflect resolution of the initial vasoconstriction phase. This may have been followed by a vasodilatory phase leading to a reperfusion injury of the previously ischemia‐injured areas explaining the patient's posterior fossa edema, impending herniation, and neurological deterioration, necessitating emergent neurosurgical intervention. In a case of an alpaca with xylazine inadvertently injected intra‐arterially, the post‐mortem histology of the brain revealed perivascular hemorrhage, fibrinoid necrosis, necrotic vasculature, and cerebro‐cortical edema. ¹⁶ This analysis aligns with the microvascular constriction that resembled embolic strokes on CT imaging, and then evolved into vasogenic posterior fossa edema.

Given the increase in fatal overdose cases involving xylazine, xylazine toxicity should be considered in all patients where opioid use is suspected and in those with new onset neurologic symptoms, respiratory depression, skin wounds, metabolic derangements, and rhabdomyolysis. In hospitals with high local prevalence, xylazine can be added to toxicology screens that test for opioids, if costs are not prohibitive. This may add clarity regarding the clinical course for those with xylazine toxicity. More studies are needed to further understand the systemic effects of xylazine in humans, and more research is needed to evaluate the potential use of atipamezole in humans and investigate other possible human reversal agents.

CONFLICT OF INTEREST STATEMENT

George L. Anesi reports payments for authoring chapters for UpToDate and expert witness consulting and reports that his spouse is employed by the U.S. Food and Drug Administration (FDA). All other authors declare no conflicts of interest.

Nwodim O, Karsalia R, Heslin ME, et al. Opioid‐related xylazine toxicity manifesting as myonecrosis, rhabdomyolysis, multifocal ischemic cerebral infarcts, and cerebral edema. JACEP Open. 2024;5:e13187. 10.1002/emp2.13187