Methadone poisoning has become more common in the pediatric population due to extensive use of methadone maintenance therapy (MMT). It is associated with decreased level of consciousness, coma, respiratory distress and cardiac intoxication. The cardiac complications have been reported to be QT prolongation, torsade de pointes, coronary artery disease, arrhythmia, stress cardiomyopathy and death. We herein report two pediatric patients with accidental methadone poisoning who developed stress cardiomyopathy and cardiac failure. The first case was a 4-yaer-old girl and the second one was an 18-month-old girl both being accidentally poisoned with methadone syrup and were brought with decreased level of consciousness. Both were diagnosed to suffer from congestive heart failure based on echocardiography. However, the first case passed away despite appropriate treatment, while the second one survived the condition and was discharged with good condition and was symptom free at 6-month follow-up

Amir Hossein Pourdavood

Khatereh Dehghani

Mohammad Khajouei

Mohammad Shojaie

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Archives of Academic Emergency Medicine. 2019; 7 (1): e22CASE REPORTStress Cardiomyopathy (Takotsubo syndrome) FollowingAccidental Methadone Poisoning; Report of Two PediatricCasesKhatereh Dehghani1∗, Mohammad Shojaie2, Amir Hossein Pourdavood3, Mohammad Khajouei41. Department of Cardiology, Jahrom University of Medical Sciences, Jahrom, Iran.2. Cardiology Department, Non-communicable Research Center, Jahrom University of Medical Sciences, Jahrom, Iran.3. Department of Surgery, Kerman University of Medical Sciences, Kerman, Iran.4. Nanotechnology Research Institute, Chemical Engineering Department, Babol (Noshirvani) University of Technology, Babol, Iran.Received: November 2018; Accepted: December 2018; Published online: 9 March 2019Abstract: Methadone poisoning has become more common in the pediatric population due to extensive use of methadonemaintenance therapy (MMT). It is associated with decreased level of consciousness, coma, respiratory distressand cardiac intoxication. The cardiac complications have been reported to be QT prolongation, torsade depointes, coronary artery disease, arrhythmia, stress cardiomyopathy and death. We herein report two pediatricpatients with accidental methadone poisoning who developed stress cardiomyopathy and cardiac failure. Thefirst case was a 4-yaer-old girl and the second one was an 18-month-old girl both being accidentally poisonedwith methadone syrup and were brought with decreased level of consciousness. Both were diagnosed to sufferfrom congestive heart failure based on echocardiography. However, the first case passed away despite appro-priate treatment, while the second one survived the condition and was discharged with good condition and wassymptom free at 6-month follow-up.Keywords: Methadone; toxicity; cardiomyopathy; pediatrics; case reportsCite this article as: Dehghani Kh, Shojaie M, Pourdavood A H, Khajouei M. Stress Cardiomyopathy (Takotsubo syndrome) Following Acci-dental Methadone Poisoning; Report of Two Pediatric Cases. Arch Acad Emerg Med. 2019; 7 (1): e22.1. IntroductionMethadone is a synthetic opioid which was first introducedin Germany between 1937 and 1939. A long half-life of 25to 52 hours and high analgesic effects, makes methadonesuitable for maintenance therapy in opium addicts and iscurrently used as the basis of withdrawal management asmethadone maintenance therapy (MMT) (1). Methadonepoisoning is among the catastrophic intoxications with awide range of clinical presentations including decrease inthe level of consciousness, coma, apnea, respiratory suppres-sion, and death (2). In recent years, a significant rise in theuse of different forms of methadone (tablet and syrup) in Iranhas led to increase in reported rates of accidental poisonings∗Corresponding Author: Khatere Dehghani; Cardiology Department, JahromUniversity of Medical Sciences, Jahrom, Iran. PO Box: 74148-46199 Tel/Fax:+98-715-4340405 Email: kh.dehghani@jums.ac.irespecially in pediatric populations (3, 4). Methadone over-dose in children has been associated with respiratory dis-tress, cardiac toxicity and decreased level of consciousness. Ithas also been associated with nausea and vomiting, myosis,dyspnea and early seizures (5, 6). Respiratory suppressionhas been reported to be the most lethal complication ofmethadone intoxication, which is initialized approximately12 hours after drug ingestion (7). A common cardiac mani-festation in methadone overdose is QT prolongation, whichcan lead to torsade de pointes and may result in death (8).Other effects include changes in QT dispersion, pathologi-cal U waves, stress cardiomyopathy (Takotsubo syndrome),Brugada-like syndrome, and coronary artery diseases (9). Weherein report, two cases of stress cardiomyopathy in pedi-atrics following methadone poisoning.This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0).Downloaded from: http://journals.sbmu.ac.ir/aaemKh. Dehghani et al. 22. Case presentation2.1. Case 1A 4-year-old girl was brought to our emergency departmentwith decreased level of consciousness since an hour be-fore. She was the second child of the family whose fa-ther was an opium addict on MMT. The methadone hadbeen kept in a bottle like pediatric syrup bottle and the girlwas mistakenly given methadone instead of cough syrup byher mother. Upon arrival she had a Glasgow coma score(GCS) of 7/15, a heart rate of 145 bpm, a respiratory rate of32 breaths/minute, blood pressure of 132/76 mmHg and atemperature of 36.8◦C with an oxygen saturation of 85% inroom air. Her pupils were myotic and responsive to lightand other examinations were within normal limits, so treat-ment by naloxone (0.1 mg/kg) was started for her. Sincethere was no response to the initial therapy, she was ad-mitted to the intensive care unit (ICU) and maintenancenaloxone (0.16 mg/kg/h) was started. Her electrocardiogramshowed tachycardia with QT interval of 440 milliseconds andST segment elevation in aVR and T wave inversion V1, V2and V3 (Figure 1). Laboratory investigations revealed whiteblood cell (WBC) count of 31,800 /mm3, hemoglobin of 11.9mg/dL, platelet count of 291,000/mm3, blood urea nitrogen(BUN) of 24 mg/dL, creatinine (Cr) of 1.7 mg/dL, sodiumof 133 mEq/L, potassium of 6 mEq/L, blood sugar of 113mg/dL, calcium of 8.9 mg/dl, creatine phosphokinase (CPK)of 32,000 IU/L, lactate dehydrogenase (LDH) of 6,030 IU/L,troponin of 6.18 U/L, prothrombin time (PT) of 24.4 sec, par-tial thromboplastin time (PTT) of 48 second, SGOT of 123U/L and SGPT of 1545 U/L.Transthoracic echocardiography revealed left ventricularejection fraction of 25% with akinesia of posterior wall andhypokinesia of septum. She was diagnosed with stress car-diomyopathy and acute heart failure and thus the manage-ment of heart failure including diuretics and inotropes wasstared for her. On the second day of admission, she de-veloped respiratory arrest and thus was intubated and con-nected to the ventilator with GCS of 3/15. Brain CT-scanshowed bilateral cerebellar infarction and edema and diffusebrain edema. Neurologist was consulted and medical man-agement of intracranial hypertension was started. The pa-tient received hypertonic saline (5mg/kg as bolus dosage and3mg/kg every 6 hours) and mannitol (1 mg/kg/dose). How-ever, unfortunately she died on the third day despite inten-sive care management.2.2. Case 2An 18-month-girl was transferred to our center from a pri-mary healthcare center due to decreased level of conscious-ness several hours prior to presentation. She was reportedto be treated with 3cc of methadone solution by mistakeFigure 1: The 12-lead electrocardogram (ECG) of the first patientdemonstrating tachycardia with QT interval of 440 milliseconds andST segment elevation in aVR and T wave inversion V1, V2 and V3.instead of diphenhydramine because of coryza signs andsymptoms. On admission to the primary center, she had aGCS of 14/15, a heart rate of 135 bpm, a respiratory rate of 26breaths/minute, blood pressure of 127/67 mmHg and a tem-perature of 36.8◦C with an oxygen saturation of 98% in roomair. Her pupils were myotic with response to the light. Withthe primary impression of methadone poisoning, naloxone(0.1 mg/kg) had been administered in the primary centerand then she was transferred here. She was also reported tohave had 2 episodes of tonic-clonic convulsions in the am-bulance during the transfer for which diazepam (0.1 mg/kg)was administered. On admission to our center, she had GCSof 8/15 and she had bradypnea with abdominal respirationand O2 saturation of 84% without oxygen supplement, bloodpressure of 117/67 mmHg, a temperature of 37.5◦C with my-otic pupils that were reactive to light and upward plantarreflex (Babinski), so naloxone infusion was continued (0.16mg/kg/h). She was intubated and transferred to ICU. Shehad two episodes of tonic clonic convulsion for which mi-dazolam infusion was started (0.05 mg/kg/hr). Laboratoryexamination revealed WBC count of 18,000/mm3 (88%PMN,11%Lymphocyte), hemoglobin of 8.6 mg/dL, platelet countof 390,000/mm3, BUN of 18 mg/dL, Cr of 0.7 mg/dL, sodiumof 140 mEq/mL, potassium of 4.7 mEq/L, blood sugar of 102mg/dL, CPK of 3,050 IU/L, LDH of 2,375 IU/L, PT of 20 sec-ond, PTT of 28 second, SGOT of 6220 U/L, SGPT of 5740 U/Land CRP of 73 mg/L. The ECG also showed sinus tachycardiaand prolonged QT interval (Figure 2). On the second day, shehad another episode of convulsion with decrease in O2 sat-uration. She developed bilateral fine rales in lung examina-tion in favor of pulmonary edema, so infusion of furosemide(1 mg/kg q2h) was started. Chest radiography revealed pul-monary edema. Brain CT scanning demonstrated a smallThis open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0).Downloaded from: http://journals.sbmu.ac.ir/aaem3 Archives of Academic Emergency Medicine. 2019; 7 (1): e22Figure 2: The 12-lead electrocardogram (ECG) of the second pa-tient demonstrating sinus tachycardia and prolonged QT-interval.area of ischemia and hydrocephaly.In echocardiography, ejection fraction of 15% with diffusehypokinesia and mild mitral valves regurgitation has beenshowed. She was diagnosed to suffer from stress cardiomy-opathy for which management of heart failure was started.After 3 days of conservative management with naloxone (0.1mg/kg/dose) and phenobarbital (0.15 mg/kg q12h) the pa-tient developed spontaneous respiration and was extubated2 days later. Her GCS increased to 14/15 and echocar-diography revealed normal cardiac function. She was dis-charged from the hospital on the 12th day while she wascompletely awake with normal echocardiography. On the 6-month follow-up she had normal daily activity and normalechocardiography without signs of cardiac failure. She didnot have any seizure so the anticonvulsants were tapered.3. DiscussionMethadone is a powerful analgesic drug that affects mu re-ceptors and it is majorly used for treatment of opioid addic-tion as well as for pain relief (9, 10). Poisoning by methadoneis very hazardous and may lead to death because of its irre-versible complications; in most countries it is kept in con-tainers that it is not easy for children to open and also warn-ing labels attached on the containers (11). However, in Iranthere is not any special bottle for methadone in form of syrupand it is kept in bottles like pediatric syrup bottles, so therate of pediatric methadone poisoning is relatively high anda large number of hospitalizations in emergency ward aredue to this type of poisoning (12). Unfortunately, this drugis sometimes administered to children instead of other pedi-atric syrups by mistake and because of its silent symptomssuch as drowsiness and loss of consciousness, it’s not de-tected early on by parents and they usually find out severalhours after drug ingestion, when it is too late to help thesechildren survive (3, 9). Complications of methadone toxic-ity are drowsiness, decreased level of consciousness, respira-tory failure, myosis, hypotension, acute respiratory distresssyndrome (ARDS), brain damage and other end organ dam-ages (9). Respiratory suppression is the main cause of deathin patients with methadone overdose, it may lead to severehypoxia that can result in lung and brain injury as well as re-nal and liver dysfunction (13). Some other adverse effects in-clude ataxia, hearing loss, cerebellitis and chest rigidity (14,15). The cardiac complications of methadone toxicity arerare and include QT prolongation and subsequent torsade depointes mainly because of the electrolyte imbalance (9).We herein reported two pediatric patients with methadonepoisoning who developed severe left ventricular dysfunctionand stress cardiomyopathy leading to death in one. Stresscardiomyopathy (Tako-Tsubo syndrome) is defined as leftventricular dysfunction and ECG changes that mimic acutemyocardial infarction without any evidence of involvementof coronary arteries (16, 17). It is more common in post-menopausal women and an acute medical illness or emo-tional/physical stress may typically trigger this syndrome. Ithas been demonstrated that huge release of catecholamines(maybe due to opioid withdrawal) may be responsible fordevelopment of this cardiomyopathy. Two cases of Taku-Tsubo syndrome have been reported in relation with acuteopioid withdrawal. Lemesle et al. (16), reported the firstcase as a result of methadone withdrawal secondary to drug-drug interaction. However, we observed this phenomenonin 2 pediatric cases who were admitted to our center withmethadone poisoning and the mortality rate was as high as50% in our patients. All the previously reported cases wereadults but our patients were children. Two cases of Taku-Tsubo cardiomyopathy have been reported previously, butboth of them had happened after methadone withdrawal notmethadone poisoning (16, 17). In our patients, autopsy wasnot done in the first patient to clear the cause of her cardiacdamage and the condition of the second one wasn’t suitablefor cardiac MRI to evaluate the cardiac structure and func-tion. Further evaluation on other cases is needed to clear theeffect of methadone and its metabolites on the myocardium.4. ConclusionMethadone overdose can cause cardiac injury leading to car-diac failure and death. Toxic metabolites of methadone maycause myocarditis and cardiac failure while excessive cate-cholamine release could be another explanation for this phe-nomenon especially in young children.This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0).Downloaded from: http://journals.sbmu.ac.ir/aaemKh. Dehghani et al. 45. Appendix5.1. AcknowledgementsThe authors would like to thank their colleagues, for theirsupport. We would also like to thank the patients and theirfamily for their cooperation and allowing us to publish thematerial. We would like to acknowledge the editorial assis-tance of Diba Negar Research Institute for improving the styleand language of the manuscript.5.2. Authors contributionAll authors met the four criteria for authorship contributionbased on the recommendations of the international commit-tee of medical journal editors.Authors’ ORCIDsKhatereh Dehghani: 0000-0002-7980-3265Mohammad Shojaei: 0000-0003-1312-5913Amir Hossein Pourdavood: 0000-0002-6211-5941Mohammad Khajouei: 0000-0002-0576-761X5.3. Conflict of interestNone of the authors have any conflict of interest to declareregarding the manuscript.5.4. FundingNo fund was received for the manuscript and the manuscriptis considered the authors’ own work.References1. Joseph H, Stancliff S, Langrod J. Methadone maintenancetreatment (MMT): a review of historical and clinical is-sues. Mt Sinai J Med. 2000;67(5-6):347-64.2. Boyer EW, McCance-Katz EF, Marcus S. Methadoneand buprenorphine toxicity in children. Am J Addict.2010;19(1):89-95.3. Sharif MR, Nouri S. Clinical Signs and Symptoms andLaboratory Findings of Methadone Poisoning in Chil-dren. Iran J Pediatr. 2015;25(1):e176.4. Kashani P, Safari S, Hatamabadi H, Dolatabadi AA,Manouchehrifar M, Tabrizi MD. Characteristics ofMethadone Intoxicated Children Presenting to Emer-gency Department; a Cross Sectional Study. Emergency.2017;5(1).5. Gheshlaghi F, Izadi-Mood N, Mardani A, Piri-ArdekaniMR. Dose-Dependent Effects of Methadone on QTinterval in Patients under Methadone MaintenanceTreatment. Asia Pacific Journal of Medical Toxicology.2013;2(1):6-9.6. Aghabiklooei A, Shadnia S, Hassanian-MoghaddamH, Zamani N. Acute respiratory distress syndromecaused by methadone syrup. Arh Hig Rada Toksikol.2013;64(3):439-43.7. Jabbehdari S, Farnaghi F, Shariatmadari SF, Jafari N,Mehregan FF, Karimzadeh P. Accidental children poison-ing with methadone: an Iranian pediatric sectional study.Iran J Child Neurol. 2013;7(4):32-4.8. Mayet S, Gossop M, Lintzeris N, Markides V, Strang J.Methadone maintenance, QTc and torsade de pointes:who needs an electrocardiogram and what is theprevalence of QTc prolongation? 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First case of stress cardiomyopathy as a result ofmethadone withdrawal secondary to drug-drug interac-tion. Am J Emerg Med. 2010;28(3):387.e5-6.17. Spadotto V, Zorzi A, Elmaghawry M, Meggiolaro M, Pit-toni GM. Heart failure due to ’stress cardiomyopathy’: asevere manifestation of the opioid withdrawal syndrome.Eur Heart J Acute Cardiovasc Care. 2013;2(1):84-7.This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0).Downloaded from: http://journals.sbmu.ac.ir/aaem

Stress Cardiomyopathy (Takotsubo syndrome) Following Accidental Methadone Poisoning; Report of Two Pediatric Cases

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Stress Cardiomyopathy (Takotsubo syndrome) Following Accidental Methadone Poisoning; Report of Two Pediatric Cases

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