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.

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