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Acute Lateral Myocardial Infarction Secondary to Tramadol-Induced Kounis Syndrome Suat Gormel M.D., Tolga Ege M.D., Mustafa Koklu M.D., Murat Celik M.D., Uygar Cagdas Yuksel M.D.

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S1053-0770(15)00067-1 http://dx.doi.org/10.1053/j.jvca.2015.02.001 YJCAN3200

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Journal of Cardiothoracic and Vascular Anesthesia

Cite this article as: Suat Gormel M.D., Tolga Ege M.D., Mustafa Koklu M.D., Murat Celik M.D., Uygar Cagdas Yuksel M.D., Acute Lateral Myocardial Infarction Secondary to Tramadol-Induced Kounis Syndrome, Journal of Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2015.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Acute Lateral Myocardial Infarction Secondary to Tramadol-Induced Kounis Syndrome

* Suat GORMEL, M.D. ** Tolga EGE, M.D. * Mustafa KOKLU, M.D. * Murat CELIK, M.D. * Uygar Cagdas YUKSEL, M.D.

Gulhane Military Medical Academy, School of Medicine, Department of Cardiology (*) and Department of Orthopedic and Traumatology (**), Ankara, TURKEY

Corresponding Author Murat CELIK, M.D. Associate Professor of Cardiology Department of Cardiology Gulhane School of Medicine, 06018 Etlik-Ankara, Turkey Tel: +90-312-3044261 Fax: +90-312-3044250 E-mail: [email protected]

Acute Lateral Myocardial Infarction Secondary to Tramadol-Induced Kounis Syndrome Introduction In 1991, Kounis syndrome was described as “the coincidental occurrence of chest pain and allergic reactions accompanied by clinical, laboratory and electrocardiographic findings of acute myocardial ischemia.” [1]. It is hypothesized that vasospastic angina could be induced by functional and metabolic changes in the heart caused by the release of inflammatory mediators such as histamine and leukotrienes acting upon the smooth muscle of the coronary arteries following a serious allergic insult [1, 2]. Even today, little is known about this syndrome and most of the existing data comes from case reports. Several drugs, conditions, environmental exposures, latex, foods, venom and toxins have been reported to cause this rare-life threatening syndrome. Although activation of mast cells and the systemic release of histamine are common side effects of morphine, in the literature, there are only two case reports of Kounis Syndrome induced by the administration of morphine and morphine derivatives [3, 4]. Herein, we report the case of a patient developed coronary vasospastic angina (type 1 variant of Kounis syndrome) immediately after the administration of tramadol, which was a rare presentation of this syndrome. Case report A 45-year-old woman was admitted to our orthopedic clinic with a painful and swollen right ankle due to a bimalleolar fracture after a sidewalk fall accident occurred in the evening at 8 o'clock. The fracture was successfully treated with an open reduction internal fixation in the morning the next day. Bupivacaine was used in spinal anesthesia. Non-steroidal anti-inflammatory drug (NSAID) was used to control pain. Any adverse event was not observed in the operating room or in the recovery room. During clinical follow-up in the patient room (almost about 6 hours after the surgery), 100 mg tramadol was given by slow IV

diluted infusion to reduce the patient’s ongoing pain despite NSAID. Just immediately after the administration of the tramadol IV infusion (almost 5 minutes later), she began to present feeling of instability, excessive sweating, palpitations, retrosternal chest pain, dyspnea, nausea and vomiting. The tramadol infusion was discontinued. Her past medical history was unremarkable with no cardiovascular risk factors, systemic illness or atopic disease. However, the electrocardiogram (ECG) showed 2.5 mm ST-segment elevation in leads DI and aVL and marked reciprocal ST-segment depression in leads DIII and V3–V5 and QTc was 436 msn (Fig. 1). Then, the patient was transferred to the coronary care unit. Physical examination revealed a blood pressure of 100/59 mmHg with a regular pulse of 122 beats/min, respectively, and generalized erythema and urticarial skin rashes as signs of allergic reaction. Cardiovascular and respiratory auscultation findings were unremarkable. Troponin I level (4.101 ng/ml) and CK-MB level (42 IU/L) were high. A transthoracic echocardiography examination revealed lateral wall hypokinesia and normal left ventricular systolic function with an ejection fraction of 55%. Standard treatment for acute coronary syndrome with subcutaneous injection of 4000 IU enoxaparin, a loading dose of 180 mg ticagrelor and 100 mg acetylsalicylic acid were administered. During the follow-up in the coronary care unit, the patient’s chest pain was relieved and ST segment elevation was resolved (Fig. 2). A coronary angiography was performed immediately after transferring to the coronary care unit and revealed normal right and left coronary arteries (Fig. 3). Thus, her medical therapy was continued with analgesic and 75 mg/ day clopidogrel for 1 month. No recurrent angina was observed during hospitalization, and she was discharged on the fourth day without any symptoms. T-wave abnormality was observed on subsequent ECG (flattening of T wave on lead DI and T-wave inversion on lead aVL). Transthoracic echocardiography examination was repeated before the discharge and revealed that regional wall motion abnormality was vastly improved.

We explored the other possible allergic medications prior to the tramadol, which might have gone unnoticed. She had received 2 grams IV cefazolin as premedication and NSAID to control the pain, but any symptom of a possible allergic reaction was not observed during the administration of these drugs. We suggested that the hypersensitivity reaction following IV administration of tramadol probably caused the anginal attack and ECG changes and, thereby, the diagnosis of Kounis syndrome was made. The patient was recommended to undergo an allergy testing. Discussion One of non-atherosclerotic coronary artery diseases is allergic myocardial angina pectoris or myocardial infarction syndrome, which is known as “Kounis Syndrome” [1]. The main pathophysiological mechanism is thought to be concomitant coronary artery spasm or atherosclerotic plaque rupture associated with allergic reactions [5]. During hypersensitivity or anaphylactic reactions, mast cell activation causes vasospastic and inflammatory response on the coronary endothelium [5]. Three types of Kounis Syndrome have been described. In type-I variant, patients have normal coronary arteries without any predisposing cardiovascular risk factors, whereas type II variant includes patients with established coronary artery disease [6]. The type III variant has been proposed recently and is associated with drug-eluting stent thrombosis [7]. Tramadol, a centrally acting analgesic, is a weak opioid analgesic with moderate potency. Tramadol is currently recommended for the treatment of patients with moderate to severe pain, especially for postoperative pain, in clinical practice and analgesia with tramadol has been frequently well accepted by the patients. Due to its minor cardiovascular side effects, tramadol has also been used for the control of pain associated with acute myocardial infarction. Nonetheless, in their animal study, Zhang and Gua [8] observed that tramadol pretreatment reduced the infarct size parallel with down-regulation of the expression and

activation of NF-kB in the myocardium and might be beneficial for clinical applications in the early stage of acute MI. However, to the best of our knowledge our case is the first case report of Kounis Syndrome following exposure to tramadol. There is no specific test for the diagnosis of Kounis syndrome. The diagnosis is extremely clinical, and is based on the identification of signs and symptoms suggestive of allergic reaction and ECG changes, laboratory, echocardiography, and angiography findings suggestive of coronary event should also be encountered coinciding in time. As well as laboratory findings indicating cardiac damage, tests specify the possible allergic reactions (serum tryptase, histamine, arachidonic acid derivatives, interleukins, tumor necrosis factor, complement, eosinophilia, total and specific immunoglobulin E) are the other important analyses used in the diagnosis of Kounis syndrome [9]. Serum tryptase is the most abundant secretory granule-derived serine proteinase contained in mast cells, and elevated levels of serum tryptase occur in both anaphylactic and anaphylactoid reactions. It is more useful and practical marker of mast cell activity than plasma histamine parameter for diagnosing anaphylaxis, offering a sensitivity of 73% and a specificity of 98% [1, 10]. However, a negative test does not rule out the possibility of allergic reaction, because the blood sample should be taken between the first and second hour after onset of symptoms. Since our central laboratory of our institute does not have tryptase testing ability, we could not measure the serum tryptase level. We believe that the lack of analysis of immunological laboratory markers is the most significant limitation supporting the diagnosis of Kounis syndrome in our case. Skin prick tests may also be helpful for diagnosis. The clinical history is essential for establishing a cause-effect relationship in time with the possible triggering factor. Symptoms and signs of allergic reaction may include hypotension, pruritus, urticaria, dyspnea, wheezing, nausea, vomiting, and, in severe cases, angioedema after contacting with allergen.

Kounis syndrome should be differentiated from other causes of angina-like chest pain such as pericarditis, pericardial effusion, aortic dissection or acute pulmonary embolism. Also, acute coronary syndrome in patients with non-atherosclerotic coronary artery disease may be the consequence of Prinzmetal Angina, coronary artery embolism, Tako-tsubo cardiomyopathy, cocaine abuse and spontaneous coronary artery dissection. In these patients, after the initial ischemic insult, late coronary angiography usually reveals normal epicardial coronary vessels. Also, the possible allergic antecedents of the patient must be explored (especially the recent use of medications that may have gone unnoticed). It may be challenging to make a differential diagnosis between Prinzmetal angina (pure variant angina) and Kounis syndrome, especially type I variant [5]. In both conditions, the underlying pathophysiology resulting in myocardial ischemia is similarly the contraction of coronary artery. Stimuli that cause vasospasm in Prinzmetal angina are similar to factors released during allergic reactions [11]. There are no definite diagnostic criteria to differentiate Kounis syndrome from other causes. Despite the coronary angiography with the injection of provocative agents such as ergonovine, methylergonovine or acetylcholine into the coronary artery is the gold standard for the diagnosis of Prinzmetal Angina, it has been shown that ergometrine maleat was related to coronary spasm in allergic acute coronary events [12]. Nonetheless, degranulated mast cells and immunological markers such as tryptase and histamine blood levels are shown to be elevated not only in allergic acute coronary syndromes but also in the coronary plaque rupture areas of patients with recent myocardial infarction of non-allergic origin [13]. Therefore, it was hypothesized that these immunological mediators are unable to differentiate this syndrome from a conventional ischemic event. However, it should not be forgotten that very evident increases of these immunological mediators could probably be regarded as a finding of Kounis syndrome, rather than Prinzmetal Angina. Acute psychological or mental stress can trigger mast cell degranulation in the heart through local

corticotropin releasing hormone (CRH) acting or neuropeptide neurotensin release and associated with cardiac events [11, 14]. Takotsubo cardiomyopathy is a stress-induced acute cardiac disorder affecting the left ventricle, producing hyperkinesia of the ventricle base, hypokinesia of the apex and mid-zone and characterized by cardiac symptoms, and ECGchanges, but no coronary artery stenosis and no other causative disease [15]. These alterations would be caused by the action of immunological mediators in the same way as in Kounis syndrome and differentiation of Kounis syndrome from this stress-induced Takotsubo cardiomyopathy may also be required. Our patient showed no preceding emotional or psychological stress, and echocardiography did not revealed development of apical left ventricle ballooning. Thus, we excluded the possibility of stress-induced acute coronary events. Consequently, it seems not easy to distinguish these two situations from Kounis syndrome. However, it might be postulated that signs and symptoms of a systemic allergic reaction associated with clinical, laboratory and electrocardiographic findings of acute myocardial ischemia are in favor of the Kounis syndrome. In conclusion, the type-I variant of Kounis Syndrome following exposure to tramadol is most likely responsible for leading to acute lateral myocardial infarction in the present case. Not only cardiologists, but also all physicians should be aware of the allergic myocardial angina or infarction and potentially harmful effects of tramadol, which currently recommended as a basic analgesic for the treatment of patients with moderate to severe pain.

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Figure Legends Figure 1. Electrocardiogram immediately after the initiating the tramadol infusion. Figure 2. Electrocardiogram after the patient’s chest pain was relieved Figure 3. Coronary angiography showing normal left (A) and rights coronary (B) arteries

Fig 1

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Acute Lateral Myocardial Infarction Secondary to Tramadol-Induced Kounis Syndrome.

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