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The diagnosis and management of poisoning is essential in critical care medicine. Traditionally, these conditions fall under the category of toxidromes that are the signs and symptoms associated with a particular class of poisons. However, there has been a steady increase in designer drugs and contaminants of recreational drugs themselves. Examples of adulterants in cocaine include the local anesthetic benzocaine and the anti-parasitic levamisole. This paper presents the clinical signs, laboratory findings, and treatment of patients who have been exposed to these substances. Admissions to the ICU related to substance abuse is, unfortunately, a common global issue. Identification of the illicit drug on clinical presentation is often difficult. These substances often fall into multiple categories of toxidromes, the signs and symptoms associated with a particular class of poisons 2. Polysubstance abuse is common. Laboratory tests can confirm the most common illicit substances but often will not identify altered forms 5. Our experience in a trauma center encompasses patients with substance abuse issues, but we had sparse knowledge of contaminants before caring for the patient in the clinical example below. In this paper we present examples illicit drug contaminants, a little-known subject for critical care physicians. Cocaine is one of the most common illegal psychostimulant drugs 4 , 6 , 7. Cocaine blocks the transporters for dopamine, norepinephrine, and serotonin 8. With this blockade, there is continued stimulation by monoamines at the pre- and post- synapses to create euphoria that leads to addiction. Symptoms include tachycardia, hypertension, hyperthermia, and agitation 7. The long list of sequelae includes myocardial and cerebral infarctions. Acute kidney injury may be related to decreased renal blood flow from vascular smooth muscle constriction and rhabdomyolysis 9. Cutaneous vasculopathy with rheumatologic features including antineutrophil cytoplasmic antibodies ANCA can occur Adulterants in seized cocaine samples include levamisole, phenacetin, lidocaine, imidazole, and caffeine 11 — Each of these compounds themselves will cause pathologic changes like cocaine making additional diagnoses difficult Table 1. Levamisole is an antihelminthic in widespread veterinary use. It had been used as an adjuvant chemotherapy agent but was withdrawn from the US market in after side effects of agranulocytosis, cutaneous vasculopathy, and leukoencephalopathy were identified 14 — The mechanism for euphoria includes the metabolism to aminorex, an amphetamine-like substance once used as a diet drug. Aminorex was taken off the market secondary to pulmonary hypertension Levamisole increases antibody production to various antigens by functioning as a hapten involved with isoimmune antineutrophil cell membrane antigens. Cutaneous manifestations include purpura, hemorrhagic bullae, and livedo reticularis An immune-mediated mechanism has been suggested for eosinophilic inflammatory coronary artery pathology Local anesthetics are added to cocaine since they have the same analgesic properties and cannot be detected as an adulterant by the drug user. Physicians are familiar with lidocaine used as an antidysrhythmic and local anesthetic controlled by the FDA and in the over-the-counter topical analgesics. What is likely unknown is that As a local anesthetic injection without epinephrine the maximum dose is 4. Clearly the drug dealers cutting cocaine with lidocaine greatly exceed this maximum. Overdose results in negative inotropy, vasodilatation, seizures, and respiratory depression Hypercapnia and respiratory acidosis exacerbate central nervous system depression. Benzocaine is rapidly absorbed across mucous membranes. Methemoglobinema results from the oxidation of the iron in hemoglobin to the ferric state. It undergoes acetylation, oxidation, and N-demethylation in the liver 6. Therefore, alcohol and abused drugs in addition to cocaine potentiate the effects of caffeine. Caffeine enhances the reinforcing effects of cocaine and its motivational value The combination of caffeine and cocaine makes users more likely to keep seeking out the drug than they would if they were addicted to cocaine alone. Phenacetin is an antipyretic and analgesic that is cleaved to form acetaminophen. It was removed from the market because of renal carcinogenicity. It is a negative inotrope, can generate methemoglobinemia through its metabolites, and can cause hemolytic anemia 25 — Phenacetin has no stimulant properties but is used as a cutting agent to increase the bulk of cocaine. Imidazole has fungicidal, antiprotozoal, and antihypertensive properties The most common use is as a topic antifungal such as ketoconazole. It is part of the theophylline molecule derived from tea leaves and coffee beans and acts as a central nervous system stimulant. Imidazole itself is hepatotoxic via ATP depletion in cells with mitochondrial damage. Cannabis is the most widely used psychoactive substance. Usually, the effects of decreased locomotor activity, cognitive impairment, analgesia, hypothermia, and appetite stimulation are considered of low toxicity but may be exacerbated when consumed in large doses 28 , Cutting agents in high levels, in addition to heavy metals leaching from the devices, are respiratory irritants Table 1. Vitamin E acetate is a cutting agent that has been added to marijuana oils and has been associated to vaping-associated lung injury EVALI that includes diffuse alveolar damage, bronchiolitis with organizing pneumonia, and granulomatous pneumonitis Pine rosin, a known lung irritant has been identified as an adulterant Lung examination upon presentation does not correlate with the severity of the disease that can include diffuse alveolar damage, pneumonitis, and organizing pneumonia Synthesized cannabinols are dissolved in alcohol and acetone and sprayed on plant material. Intoxication can be severe including psychosis, respiratory depression, cardiac arrest, nephrotoxity, hyperemesis, rhabdomyolysis, hyperthermia, seizures, and cerebral ischemia The most lethal adulterant of synthetic cannabinoids is brodifacoum, a vitamin K-dependent antagonist 34 , It is used to enhance the effects because of longer periods of lipid storage, hepatic metabolism, and slow release. Compared to the anticoagulation of warfarin it is times greater and has a longer half-life of 20— days Their effect is like 3,4-methylenedioxymethamphetamine MDMA; ecstasy with the blockade of dopamine and norepinephrine uptake Animal studies demonstrated that the synthetic cathinone methylenedioxypyrovalerone MDPV has greater potency than cocaine with respect to hyperactivity and cardiovascular stimulation Neurologic symptoms include agitation, paranoia, hallucinations, myoclonus, and psychosis. In addition to hyperthermia, hypertension, and tachycardia liver failure, kidney failure, and compartment syndrome with rhabdomyolysis have been reported Xylazine is a veterinary drug used as a sedative, analgesic, and muscle relaxant 38 , It has a structure that is similar to phenothiazines, tricyclic antidepressants, and clonidine. The intended use, in addition to cutting, is to enhance the sedation and analgesia of the illicit drug. Xylazine was first identified as a cutting agent in Puerto Rico and has adulterated heroin and cocaine and 38 , The contaminant of fentanyl with xylazine has been considered as the deadliest drug threat in the United States The most noted side effect of xylazine is characteristic necrotic skin ulcers that are likely caused by vasoconstriction and poor skin perfusion Based on case reports, the effects of overdosage include hypotension, bradycardia, hyperglycemia, areflexia, elevated cardiac enzymes, coma, and respiratory failure The acuity of substance abuse patients admitted to the ICU is complex but well within the realm of care addressed by intensive care physicians. Respiratory embarrassment may be related to the overdose suppression of spontaneous ventilation or pulmonary parenchymal pathology as found with EVALI. The need for tracheal intubation and mechanical ventilation is straight-forward for most of these patients and often performed before the patient arrives in the ICU. As many of the patients are polysubstance abusers, treatment of the drug effects, as well as underlying psychiatric issues , may require the use of multiple agents such as quetiapine and benzodiazepines 33 , For severe withdrawal, high dose lorazepam alone was ineffective when compared to the synergistic actions of propofol infusions with reduced lorazepam doses Acute kidney injury treatment is largely supportive 9. Restoration intravascular volume is essential since acute tubular necrosis may be related to hypovolemia resulting from poor intake, diarrhea, and vomiting. The latter is often associated with altered electrolyte levels. CPK's should be monitored to reveal rhabdomyolysis that may not be evident on physical examination. Dialysis may be necessary 9. Cardiovascular toxicity , especially with cocaine, is the most difficult life-threatening processes requiring ICU care. The evidence for pharmacologic treatment is limited for the management of tachycardia, hypertension, dysrhythmia, and coronary vasospasm in a comprehensive review of the literature Labetalol and carvedilol will control hypertension and tachycardia. Nitroglycerin is recommended for cocaine-associated chest pain and vasospasm with the risk of tachycardia Dexmedetomidine will control hypertension at high doses 1. Beta blockers will decrease heart rate as expected but are used cautiously to prevent unopposed hypertension. Esmolol is effective but will cause more hypotension when comparted to other beta blockers. Hyperbaric oxygen treat has been reported for methemoglobinemia that was refractive to methylene blue. The cardiac effects of caffeine overdose are ameliorated with dialysis. The extensive skin necrosis and infection related to xylazine is treated with appropriate antibiotics, topical treatment, and surgical debridement if needed. The management of patients requiring ICU care for toxicities related to substance abuse is challenging. The clinical pathophysiology may be related to a single drug, multiple drugs, and often adulterated illegal agents. For many of these patients, such as the one described above, supportive critical care is an easily identifiable task but comes with the cost of extensive resource management. It is critical to consider adulterants that would cause unexpected findings such as methemoglobinemia, lidocaine toxicity, necrotic skin lesions, or rhabdomyolysis in the absence of trauma or a compartment syndrome. PM and RP equally contributed to the research, writing, and editing of this manuscript. All authors contributed to the article and approved the submitted version. The author RP declared that he was an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision. The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Burden of substance abuse-related admissions to the medical ICU. Crit Care Clin. Cutting agents in cocaine: a temporal study of the period — in the northern region of Columbia. Forensic Sci Int. Cocaine adulteration. J Chem Neuroanat. Toxicology in addiction medicine. Clin Lab Med. Cocaine: an updated overview on chemistry, detection, biokinetics, and pharmacotoxicological aspects including abuse pattern. Toxins Basel. Zimmerman JL. Critical care medicine. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev. Nephrotoxic effects of common and emerging drugs of abuse. Clin J Am Soc Nephrol. Milman N, Smith CD. Cutaneous vasculopathy associated with cocaine use. Arthritis Care Res. Qualitative, quantitative and temporal study of cutting agents for cocaine and heroin over 9 years. Schneider S, Meys F. Analysis of illicit cocaine and heroin samples seized in Luxembourg from to Brazilian federal police drug chemical profiling—the PeQui project. Sci Justice. Levamisole: a common cocaine adulterant with life-threatening side effects. Agranulocytosis and other consequences due to the use of illicit cocaine contaminated with levamisole. Curr Opin Hematol. Levamisole-a toxic adulterant in illicit drug preparations: a review. Ther Drug Monit. Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters. Neurochem Int. Acute coronary syndrome after levamisole-adultered cocaine abuse. J Forensic Leg Med. Lirk P, Berde CB. Local anesthetics. White powder, blue patients: methaemoglobinaemia associated with benzocaine-adulterated cocaine. Willson C. The clinical toxicology of caffeine: a review and case study. Toxicol Rep. A case of suicide by ingestion of caffeine. Forensic Sci Med Pathol. Caffeine, a common active adulterant of cocaine, enhances the reinforcing effect of cocaine and its motivational value. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review. Br J Clin Pharmacol. Hepatocellular toxicology of imidazole and triazole antimicotic agents. Toxicol Sci. Emergency department presentations related to acute toxicity following recreational use of cannabis products in Switzerland. Drug Alcohol Depend. Unwitting adult marijuana poisoning: a case series. Clin Toxicol. E-cigarettes, vaping devices, and acute lung injury. Respir Care. Meehan-Atrash J, Rahman I. Chem Res Toxicol. Pulmonary illness related to e-cigarette use in Illinois and Wisconsin—final report. N Engl J Med. Cooper ZD. Adverse effects of synthetic cannabinoids: management of acute toxicity and withdrawal. Curr Psychiatry Rep. Kumar S, Bhagia G. Brodifacoum-laced synthetic marijuana toxicity: a fight against time. Am J Case Rep. Hemorrhagic soft tissue upper airway obstruction from brodifacoum-contaminated synthetic cannabinoid. J Emerg Med. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci. Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: a comprehensive review of the literature. Xylazine in the opioid epidemic: a systematic review of case reports and clinical implications. United States Drug Enforcement Administration. Hoffman J. Drug Zones. Human overdose with the veterinary tranquilizer xylazine. Am J Emerg Med. Antipsychotics for the treatment of sympathomimetic toxicity: a systemic review. Propofol combined with lorazepam for severe poly substance misuse and withdrawal states in intensive care unit: a case series and review. Emerg Med J. Treatment of cocaine cardiovascular toxicity: a systemic review. J Am Coll Cardiol. Dexmedetomidine as a novel countermeasure for cocaine-induced central sympathoexcitation in cocaine-addicted humans. Methemoglobinemia in the operating room and intensive care unit: early recognition, pathophysiology, and management. Adv Ther. Keywords: adulterants, cocaine, toxicity, cathinones, cannabis, illicit drugs, xylazine. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Pino rpino1 lsuhsc. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Diagnosis and management of the patient with contaminated illicit drug poisoning. Richard M. McGrew 2. Introduction Admissions to the ICU related to substance abuse is, unfortunately, a common global issue. Cocaine Cocaine is one of the most common illegal psychostimulant drugs 4 , 6 , 7. Table 1. Acute effects of cocaine and cannabis contaminants. Keywords: adulterants, cocaine, toxicity, cathinones, cannabis, illicit drugs, xylazine Citation: Pino RM and McGrew PR Diagnosis and management of the patient with contaminated illicit drug poisoning.

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