The authors of this report present 3 cases of synthetic opioid intoxication complicated by the concomitant presence of the additive xylazine, a nonopioid sedative analgesic and muscle relaxant used in veterinary medicine that potentiates respiratory depression associated with the opioid toxidrome. Three exposed children presented with severe signs and symptoms, 2 of whom experienced cardiac arrest, a need for continuous naloxone infusion or multiple naloxone doses, or mechanical ventilation to treat respiratory failure after their exposures. Additives were detected in urine studies only through the performance of specialized toxicology testing. Detection of xylazine among adult overdose deaths has recently increased sharply, particularly across the northeastern United States. Adulteration by xylazine is an emerging public health threat nationally. Our report reveals that pediatricians should be aware of sentinel drug trends among adults, including the emerging types of illicit, synthetic, or counterfeit formulations of recreational substances, because children may be harmed because of accidental or intentional exposure. Children exposed to dangerous substances also need child protection services that may entail safe relocation outside of the home and the referral of affected caregivers to necessary substance use treatment services. Given epidemic drug use among adults, pediatricians should be competent to recognize common toxidromes and be aware that signs and symptoms may be potentiated by synergistic novel additives or polysubstance exposures. Importantly, standard urine drug screens may not detect synthetic opioid derivatives or contributing additives, so that diagnosis will require specialized toxicology testing.
Substance use and overdose deaths among US adults persist as major public health crises despite decades of robust prevention efforts at local, national, and regional levels. Whereas cocaine was implicated in deaths across the early 2000s, opioid-related fatalities have predominated over the last 15 years, driven largely by the misuse of prescription opioids (2007–2013), a resurgence of heroin use (2014–2015), the introduction of “designer” opioids, including synthetic derivatives such as fentanyl (2016 to present), and polysubstance use.1 Synthetic opioids are now the most common substances involved in overdose deaths nationally; fentanyl accounted for nearly 60% of all fatalities in 2017, up from 14% in 2010.2 Beyond being nearly 1000 times more potent than heroin and 50 to 100 times more potent than morphine, illicitly manufactured synthetic opioids also heighten overdose fatality risk because of frequent adulteration by cocaine, methamphetamine, novel benzodiazepines, synthetic cannabinoids, and other additives that increase bulk, characterize the specific “stamp” or brand of product in the illicit retail market, facilitate drug delivery, and potentiate the illicit substance’s pharmacologic effects.2–5
The State Unintentional Drug Overdose Reporting System compiles data on overdose fatalities across 38 states and Washington DC and has identified recent marked increases in xylazine detection in 2019.6 Xylazine (C12H16N2S) is a nonopioid sedative analgesic and muscle relaxant commonly used in veterinary medicine concomitantly with ketamine or barbiturates to sedate large animals.7,8 Xylazine is a potent α-2 adrenergic agonist that inhibits the neurotransmitter release of dopamine and norepinephrine at the neuronal synapse and produces central nervous system depression. Although xylazine is not approved for human use, this drug has increasingly been identified in illicit substances (including the popular “speedball” admixture of heroin, cocaine, and xylazine) and was first described as a potent, prevalent additive in the unregulated drug supply of Puerto Rico nearly 2 decades ago.7,9–11 Known colloquially as “anastesia de caballo” (horse tranquilizer), “tranq,” or “sleep cut,” synthetic opioid formulations containing xylazine (“tranq dope”) are increasingly sought-after by people who use illicit substances for recreation; the addition of xylazine reportedly improves and prolongs the duration of opioid-associated euphoria.7,12 Notably, by interacting with α-adrenergic receptors, xylazine exhibits pharmacodynamics distinct from opioids, whose metabolites primarily interact with the body’s μ opioid receptors.4 Clinical effects of opioids are potentiated by the pharmacologic effects of xylazine, but, given that opioids and xylazine act through different mechanisms, effects from xylazine (bradycardia, hypotension, central nervous system and respiratory depression) may not be reversed by naloxone. Exposure to clinically synergistic, opioid–xylazine formulations is therefore particularly dangerous; increased risk of overdose death may result from naloxone-resistant potentiation of respiratory depression and cardiovascular effects.4,12 We present 3 cases of children exposed to xylazine in the Delaware Valley region and discuss clinical management, toxicology testing, and child protection implications.
Case 1
A 15-month-old male toddler with a medical history notable for prenatal substance exposure (maternal use of amphetamines, fentanyl, cocaine, methadone) and neonatal opioid withdrawal syndrome was transferred to the PICU from an external hospital emergency department (ED) after cardiac arrest. His mother picked him up from daycare earlier that day; he was well-appearing during the drive home. After their arrival home, his mother found him in his car seat unresponsive, limp, and blue. His mother drove immediately to the ED; bradycardia and apnea prompted cardiopulmonary resuscitation (CPR). After 5 minutes of CPR and trial administration of nasal naloxone, the return of spontaneous circulation preceded increased alertness and responsiveness; clinical suspicion was high for opioid intoxication. Within several minutes, bradycardia and a decreased level of consciousness recurred, prompting the administration of a second naloxone dose. Naloxone continuous intravenous infusion was initiated before transfer to PICU; infusion was discontinued <6 hours later. The toddler’s mother denied recent personal use of substances. However, the toddler’s immunoassay urine drug screen was positive for opioids. Opioid confirmation testing by gas chromatography-mass spectrometry (GC-MS) identified morphine and noroxymorphone metabolites (noroxymorphone is a known metabolite of naloxone). The child had not received morphine as a hospital treatment and its identification raised suspicion of additive or polysubstance exposure. Fentanyl and norfentanyl metabolites and xylazine were identified by GC-MS on an expanded drug panel performed on a urine specimen obtained within 12 hours of presentation. We reported our safety concerns to child protective services (CPS) and he was discharged to foster care because of parental substance use. On further investigation, the mother had suffered a near-fatal synthetic opioid overdose 1 week before. CPS facilitated the linkage of his mother to a substance use disorder treatment program.
Case 2
A 7-month-old male infant with a medical history of prenatal substance exposure (maternal use of amphetamines and methamphetamines) was reportedly acting normally at home with his mother. She heard a “thump” in the next room and found him unresponsive on the floor. Emergency medical services (EMS) were contacted and, after arrival, noted pinpoint pupils and decreased respirations (described as “agonal”) but a normal heart rate. EMS administered nasal naloxone with immediate increased responsiveness. On arrival at the ED 45 minutes later, he was crying and breathing normally, with mild tachycardia and pinpoint pupils. Within an hour, signs of decreased responsiveness and bradypnea recurred; he was administered intravenous naloxone with good clinical response. Two hours later, he again developed decreased responsiveness and bradypnea and again responded to intravenous naloxone. After recurrent decreased responsiveness an hour later, naloxone intravenous infusion was started and continued for 14 hours. Episodic tachycardia and hypertension were noted, but no bradycardia or hypotension. His urine drug screen was negative; because of high clinical suspicion of opioid exposure, specialized toxicology tests were ordered. Fentanyl, norfentanyl, and xylazine were identified by GC-MS on an expanded drug panel obtained within 1 hour of hospital presentation. In this case, also, we reported our safety concerns to CPS, which coordinated discharge to foster care because of parental substance use. CPS again facilitated the linkage of his mother to a substance use disorder treatment program.
Case 3
A 19-month-old male infant with a medical history of prenatal substance exposure (maternal opioid use) and neonatal opioid withdrawal syndrome was transferred to PICU from an external hospital ED after cardiac arrest of uncertain etiology. The toddler was in his car seat in his mother’s motor vehicle when she noted labored breathing and found him cyanotic. A bystander assisted with CPR until EMS arrived; he was unresponsive, hypothermic, and hypotensive and was intubated before arrival at the ED. Results of basic laboratory studies and head computed tomography were unremarkable; a lumbar puncture was performed, and antibiotics were initiated; however, they were quickly discontinued because of a lack of identified infectious etiology. The toddler was extubated and returned to baseline mental status within 24 hours, prompting suspicion of ingestion as a potential etiology of his clinical signs. He had not received naloxone. The urine drug screen results were negative; however, specialized toxicology testing (expanded drug panel) using a urine specimen obtained within 3 hours of presentation was positive for acetyl fentanyl (illicit fentanyl metabolite) and xylazine by GC-MS. We reported our safety concerns to CPS, and he was discharged with a safety plan in place for supervised contact with his mother, who was actively receiving treatment for substance use disorder.
Discussion
Pediatricians should be aware of sentinel drug trends among adults so that they can recognize key signs and symptoms among exposed children and institute appropriate diagnostic testing and clinical management. Adult data from 10 jurisdictions, representing all 4 major US census regions, indicates that the concomitant presence of xylazine in drug overdose fatalities increased by nearly 50% from 2019 to 2020 alone,12 with the highest prevalence observed in Philadelphia (xylazine present in 25.8% of overdose deaths in 2020), followed by Maryland (19.3% in 2021) and Connecticut (10.2% in 2020).12 Across these 4 census regions, the Northeast experienced the highest prevalence, with a growing magnitude of the geographic distribution of xylazine positivity in overdose deaths spreading west in parallel with the trajectory of illicitly manufactured fentanyls in recent years.12,13 Xylazine is likely underreported in its national prevalence because of variability in testing and awareness.4,7
Xylazine was first synthesized in 1962 as an antihypertensive drug in Germany by Bayer Corporation and has since been marketed as Rompun, Anased, Sedazine, and Chanazine, approved for use in dogs, cats, horses, deer, and elk.4,12 Although structurally similar to tricyclic antidepressants, phenothiazines, and clonidine, the pharmacologic properties of xylazine are most similar to clonidine. Xylazine binds to α-2 adrenergic receptors in the brainstem, thereby inhibiting norepinephrine release and decreasing sympathetic outflow; xylazine also decreases acetylcholine release.14 Resembling clonidine intoxication, signs and symptoms after xylazine exposure include lethargy, bradycardia, apnea and respiratory depression, dry mouth, hypothermia, and coma.14,15 Pharmacokinetic parameters,well-established in nonhuman species, indicate xylazine is absorbed, metabolized, and eliminated extremely rapidly.4,16,17 Pharmacokinetic research utilizing dogs, sheep, horses, and cattle indicates short distribution and elimination half-lives. Peak plasma concentrations occur in 12 to 14 minutes, and the drug is undetectable within a few hours4,18 ; rapid clearance in humans is also theorized. In our 3 cases, xylazine was identified in urine specimens obtained within 12 hours of hospital presentation.
Several cases of xylazine intoxication in adolescents and adults have been reported in association with accidents, attempted poisoning, or recreational use.10,14,17,19,20 This case report notably describes the unintended effect of novel drug trends on young infants and toddlers. In cases of sudden pediatric cardiorespiratory arrest or naloxone-resistant clinical symptomatology, toxic opioid exposures complicated by xylazine adulterants should be on the differential diagnosis. Management is largely supportive because no specific antidote to xylazine exists for human use; atropine, intravenous fluid resuscitation, and intubation may be needed when signs are refractory to naloxone treatment.21
Standard urine drug screen results may be negative for synthetic derivatives and illicitly manufactured opioids like fentanyl so that specialized toxicology testing is frequently required. Similarly, xylazine may only be detected on specialized expanded/comprehensive urine drug panels, such as those performed by commercial or forensic laboratories. A negative urine drug screen does not rule out substance exposure, and specialized testing is frequently needed to detect illicit formulations and additives. Obtaining a urine sample after initial hospital presentation and holding additional urine volumes (10 mL) for substance-specific or specialized expanded testing may be helpful. Consultation with the hospital’s child protection team, consultant medical toxicologist, or local Poison Control Center usefully guides testing.
Substance use and substance use disorder treatment trends among adults frequently predict health and household safety-related risks to children, including increased incidence of hospitalizations and ED visits.3,22 Because opioid exposures have become more common, pediatricians should explore the risks of substance exposure during anticipatory guidance in well-child visits and offer prescriptions for naloxone nasal spray, particularly among young infants and toddlers whose families are impacted by substance use.3,23,24
Identification of xylazine adulterants is diagnostic of illicit substance exposure. Involvement of hospital child protection teams and child welfare is paramount to ensure safe discharge and enrollment of caregivers in substance use disorder treatment programs.
Drs Deutsch and De Jong conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; and both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.
Comments