Hrev_master [page 84] [Emergency Care Journal 2023; 19:11320] Emergency Care Journal 2023; volume 19:11320 Abstract We report the case of a 40-year-old woman with a history of an opioid use disorder who presented to our emergency department complaining of palpitations, chest pain, and headache after the intramuscular injection of an ophthalmic solution containing tropi- camide and phenylephrine (Visumidriatic Phenylephrine® 100 mg/mL + 5 mg/mL, Visufarma S.p.A., Italy) a few hours ear- lier for a voluntary purpose. She developed cardiac toxicity with hypertension, tachycardia, and high levels of high-sensitivity car- diac troponin I, which required continuous cardiac monitoring for 48 hours with complete resolution of the cardiac damage without complications. Based on the current literature, this is the first reported case of cardiotoxicity induced by an ophthalmic solution of tropicamide and phenylephrine used intramuscularly for volun- tary purposes. Introduction Topical tropicamide and phenylephrine is a safe and effective combination widely used for pupillary mydriasis before cataract surgery in adult patients1 and even in children.2 Tropicamide is a short-acting anticholinergic agent used as a mydriatic and cyclo- plegic, that inhibits the parasympathetic constrictor muscle of the iris, with an effect starting within 15-20 minutes after instillation and lasting for 4-6 hours. Although topical ophthalmic prepara- tions are safe to use, they may cause side effects due to systemic absorption through the cornea, conjunctiva, and nasal mucosa through the lacrimal sac. The most common adverse reactions associated with tropicamide are local complications such as con- junctivitis, blepharitis, and itching; however, systemic complica- tions such as nausea, headache, shock, and anaphylaxis have also been reported.3,4 The risk of systemic adverse reactions may be reduced by using a small drop size.5 Tropicamide fails to give good pupillary dilatation when used alone, especially in patients with diabetes mellitus, dark-pigmented irides, and in the elderly, but if combined with phenylephrine, it can promptly induce maximal mydriasis resistant to the intense light of the operating microscope. Phenylephrine is a direct-acting sympathomimetic agent used topically in the eye as a mydriatic, available in concentrations up to 10%. In the literature, many reports suggest a systemic absorp- tion of this agent as a source of severe adverse drug reactions, including severe hypertension and the onset of arrhythmias, all explainable by the alfa1-adrenergic action of phenylephrine.6-11 These complications and pulmonary edema have also been report- ed in children with an incidence of 2.1%.4 For these reasons, patients should always be monitored during surgery and for a few hours after surgery to prevent and promptly treat adverse reactions to phenylephrine. In addition, multiple and frequent instillations of drops should be avoided to prevent any cumulative dosage effect in the blood due to systemic absorption.1 We herein report the case of a woman who developed cardiac toxicity after an intramuscular injection of 2.5 mL of an oph- thalmic solution containing tropicamide and phenylephrine (Visumidriatic Phenylephrine® 100 mg/mL + 5 mg/mL, Visufarma Correspondence: Erika Poggiali, Emergency Department, Guglielmo da Saliceto Hospital, Via Giuseppe Taverna 49, Piacenza, Italy. Tel.: +39.0523.303044 E-mail: poggiali.erika@gmail.com Key words: tropicamide; phenylephrine; cardiotoxicity; hyperten- sion; troponin; drug-induced toxicity. Contributions: EP and AA collected details of the case and drafted the manuscript. EP, ED, FM, AB, and SF cared for the patient. AV and GC critically revised the manuscript. All authors approved the final version and stated the integrity of the whole work. Conflict of interest: the authors declare no potential conflict of inter- est, and all authors confirm accuracy. Availability of data and materials: all data underlying the findings are fully available. Ethics approval and consent to participate: as this was a descriptive case report and data was collected without patient identifiers, ethics approval was not required under our hospital’s Institutional Review Board guidelines. Acknowledgements: the authors thank the Clinical Chemistry Laboratory Unit, Specialized Section of Toxicology, IRCCS Policlinico San Matteo Foundation in Pavia for the precious help in the management of all the patients admitted to their emergency department for intoxication. Received: 17 March 2023. Accepted: 21 August 2023. Early view: 7 September 2023. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2023 Licensee PAGEPress, Italy Emergency Care Journal 2023; 19:11320 doi:10.4081/ecj.2023.11320 Publisher's note: 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. A case of cardiotoxicity following intramuscular injection of tropicamide and phenylephrine ophthalmic solution in a drug-addicted young woman Antonio Agosti,1 Andrea Vercelli,1 Elena Demichele,1 Francesco Mariani,1 Andrea Biagi,2 Stefano Ferraro,2 Gianfranco Cervellin,3 Erika Poggiali1 1Emergency Department, Guglielmo da Saliceto Hospital, Piacenza; 2Cardiology Unit, Guglielmo da Saliceto Hospital, Piacenza; 3Academy of Emergency Medicine and Care, Pavia, Italy Non -co mmerc ial us e o nly S.p.A., Italy). To the best of our knowledge, this is the first report- ed case of cardiotoxicity induced by an ophthalmic formulation of tropicamide and phenylephrine used intramuscularly for voluntary purposes. Case Report A 40-year-old woman presented to our emergency department complaining of chest pain, palpitations, and headache after the vol- untary intramuscular (left deltoid) administration of 2.5 mL of ophthalmic solution containing tropicamide and phenylephrine (Visumidriatic Phenylephrine® 100 mg/mL + 5 mg/mL, Visufarma S.p.A., Italy) a few hours earlier for a voluntary purpose. She also reported pain at the injection site. The patient had a diagnosis of opioid use disorder treated with methadone (85 mg daily) and alprazolam (1 mg 3 times a day), and she was regularly followed in the drug and alcohol treatment outpatient clinic of our hospital. She used to inject tropicamide ophthalmic solution (Visumidriatic®) intramuscularly to achieve loss of contact with reality and altered thinking, as known side effects due to the mus- carinic blocking activity of tropicamide.12 She had never used the combined solution of tropicamide and phenylephrine before. On admission, physical examination resulted normal. No signs of infection were observed around the injection site. The body tem- perature was 36.5 ºC, blood pressure 160/90 mmHg, pulse 110/min regular, respiratory rate 16/min, and pulse oximetry 97%. The elec- trocardiogram (ECG) showed sinus tachycardia with normal P-R interval, QRS complex, and QTc. Bedside ultrasound documented an A-line pattern without pleural effusion and excluded the bladder globe. Echocardiography showed a normal cardiac ejection frac- tion (55%) with mild mitral insufficiency and no pericardial effu- sion. Laboratory data showed leucocytosis (28.470/mm3, normal range 4.000-10.000) with neutrophilia (23.430/mm3) and slightly increased C-reactive protein (1.33 mg/dL, normal range <0.5), sig- nificantly increased values of high-sensitivity cardiac troponin I (hsTnI) (279.8 ng/L, normal value <12; Beckman coulter). Coagulation times, renal function, and serum electrolytes were all in the normal range. We consulted the Pavia Poison Control Center, which con- firmed the diagnosis of drug-induced cardiac damage and indicat- ed the following recommendations: continuous ECG monitoring for 48 hours; repeat hsTnI; administration of benzodiazepines in case of agitation and/or hallucinations; monitoring of diuresis and alvus for the appearance of signs of urinary retention and constipa- tion; and antibiotics in case of signs of infection at the injection site and/or fever. The patient was hydrated with 0.9% 1000 mL of sodium chlo- ride intravenously (iv) and treated with Delorazepam 2 mg iv for agitation. We repeated the hsTnI assay at 3 and 6 hours, which was 1162 ng/L and 1124 ng/L, respectively, in the absence of chest pain, shortness of breath, and bedside ultrasound, ECG, and echocardiographic changes. Blood pressure returned to normal. On the day following her admission, the patient was completely asymptomatic. Blood tests were repeated and showed normal full blood count and C-reactive protein. Second-level toxicological tests were performed by the Clinical Chemistry Laboratory Unit, Specialized Section of Toxicology, IRCCS Policlinico San Matteo Foundation in Pavia, and revealed the presence of tropicamide in the patient’s urine (GC-MS method). After a 48-hour observation time in our emergency department observation unit, in the absence of clinical symptoms and with nor- mal ECG monitoring and echocardiography, the patient was dis- charged with a planned cardiological follow-up and the strong rec- ommendation to remain at rest, to avoid physical exertion, and not to use Visumidriatic® or Visumidriatic Phenylepfrine®, and call the emergency number in the case of palpitations and/or chest pain and/or shortness of breath. We reassessed the patient 5 days after her discharge. The patient remained asymptomatic throughout. The blood pressure and heart rate were normal. An ECG documented sinus rhythm. Echocardiography was unchanged. The hsTnI value was signifi- cantly reduced (18 ng/L). The final diagnosis was acute reversible myocardial damage due to intramuscular administration of tropi- camide and phenylephrine. Discussion and Conclusions Tropicamide is also known as a cheap alternative to heroin in Eastern Europe and the Soviet Union,13 and its misuse has increased over the last decade. Over the past 10 years, several cases of tropicamide abuse via intravenous injection have been reported in several countries, including Turkey, Italy, France, Tajikistan, and Kazakhstan, but also Italy.14 When taken in large doses, tropicamide can produce stimulant, euphoric, and hallucinogenic effects,15 with a mechanism not com- pletely understood but probably due to the block of the muscarinic receptor M4.1,16 that causes a central anticholinergic syndrome with the occurrence of agitation, often with pressured speech, delirium, and visual and/or auditory hallucinations. Some patients have been seen picking at non-existent objects on their bedsheets and/or clothes, which is likely because of visual perceptual distur- bances during delirium.17 More serious effects of anticholinergic toxicity include coma, seizures, tachycardia, and cardiac arrhyth- mias due to QRS prolongation.17 As reported in a recent review by Bellman et al.,13 the misuse of anticholinergic eye drops has become widespread among people with intellectual disabilities and mental disorders, and it should be suspected in all patients who develop an unusual array of symptoms, that include excitability, tachycardia, hyperthermia, hallucinations, delirium, dysphoria, unconsciousness, and ‘‘open eye’’ dreams when used intravenous- ly. An increasing number of cases of tropicamide intravenous injection have been reported in Europe, including Italy.14 Bersani et al. analyzed this phenomenon, which represents a serious health risk. According to the authors, it is mainly secondary to primary opioid (especially heroin) addiction and seems to be associated with the enhancement of the ‘positive’ effects of heroin, the decrease and delay of heroin withdrawal symptoms, the easy avail- ability, low costs and fast effects, and the visibility of self-reported experiences on the Internet.18 Phenylephrine is an alpha-1 adrenergic agonist used to treat hypotension, generally in the surgical setting associated with the use of anesthetics, dilate the pupil, and induce local vasoconstric- tion, depending on the route and location of administration. An intranasal formulation is used to treat congestion, and a topical for- mulation to treat hemorrhoids. Off-label uses include situations requiring local blood flow restriction, such as the treatment of pri- apism.19 The action of phenylephrine was first described in the lit- erature in the 1930s.20 Phenylephrine was granted FDA approval in 1939. Ophthalmic formulations of phenylephrine act for 3-8 hours, while intravenous solutions have an effective half-life of 5 minutes and an elimination half-life of 2.5 hours.21 Drug-induced cardiotoxicity can be observed during the administration of sympa- Case Report [Emergency Care Journal 2023; 19:11320] [page 85] Non -co mmerc ial us e o nly thomimetic agents, such as phenylephrine. Systemic phenyle- phrine acts through agonism on alpha-1 adrenergic receptors, rais- ing systolic and diastolic pressure as well as peripheral vascular resistance. Increased blood pressure stimulates the vagus nerve, causing reflex bradycardia and severe or fatal complications, such as myocardial infarction, coronary artery spasm, arrhythmias including AV block and ventricular extrasystoles, a hypertensive crisis with subarachnoid hemorrhage and pulmonary edema. As reported by Li et al., phenylephrine eye drops combined with intra- venous atropine have cardiovascular effects, such as a significant heart rate and blood pressure increase, that can be reversed by neostigmine. According to the authors, this drug combination should be used carefully for ophthalmic surgery, especially in patients with cardio-cerebrovascular diseases.22 Severe hyperten- sion and heart rate alterations have also been reported in pediatric patients undergoing ophthalmic surgery when treated with phenylephrine eye drops.4 Patients can also complain of gastroin- testinal disorders (nausea, vomiting), chest pain and dyspnea, ner- vous system manifestations (headache, nervousness, paraesthesia, tremor, excitability), diaphoresis, pallor, and piloerection.23 Overdose may be treated by supportive care and discontinuing phenylephrine, chronotropic medications, and vasodilators.19 Based on the current literature, no cases of intramuscular use of tropicamide and phenylephrine for voluntary purposes have been reported. Our patient used the combined ophthalmic solution instead of tropicamide alone, which caused acute cardiac damage with complete resolution in the absence of complications. It is well known that in patients with severe heart failure or cardiogenic shock, phenylephrine may cause worsening of heart failure as a consequence of induced vasoconstriction (increased afterload), but no cases of acute cardiac damage with spontaneous resolution have been reported in the literature. Our patient presented with a rise in blood pressure that did not induce pre-edema or pulmonary edema and did not require antihypertensive therapy, resolving with intra- venous administration of benzodiazepines for agitation. Echocardiography excluded a diagnosis of Tako-Tsubo. In conclu- sion, in our patient, the mechanism of cardiac damage is therefore unclear. This case was reported to the Pavia Poison Control Centre, which declared an alert 2 (risk of serious damage to health) accord- ing to the SNAP (Sistema Nazionale di Allerta Precoce)24 with a strong recommendation to immediately report any further case of tropicamide and phenylephrine intoxication. 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