Tramadol is an opioid analgesic and synthetic analog of codeine. Central Mu-opioid receptor agonist is the target action for tramadol. Indeed, the mu-opioid receptors have a 10-fold analgesic effect and affinity in tramadol less than codeine [1]. Tramadol is usually prescribed as a synthetic analgesic for both moderate and severe pain in primary care [1,2]. The initial dose is 25 mg and the maximum dose of 100 mg a day; the adult dose should not exceed 400 mg a day [2]. However, tramadol has less abuse and less inducing respiratory depression. Lethal side effects of tramadol are respiratory depression, serotonin syndrome, chest pain, fits, breathing difficulty, arrhythmia, and syncope [1,2]. Remarkable dizziness, facial, tongue, throat, and limb edema, delirium, severe skin rash, suicidal attempts, somnolence, vomiting, sweating, agitation, indigestion, dry mouth, diarrhea, tremor, and anorexia, are reported as other side effects [2]. Due to an increase in the use of tramadol as an analgesic drug in practical medicine, there is a coincide elevated incidence of serotonin syndrome [3]. Gormel et al. (2015) recorded a case of tramadol-induced Zavras Kounis syndrome (KS) is complicated by acute lateral myocardial infarction (MI) [4]. Serotonin syndrome symptoms usually occur within several hours of taking a new drug or increasing the dose of a drug you're already taking. Signs and symptoms include agitation or restlessness, confusion, tachycardia, hypertension, mydriasis, loss of muscle coordination, twitching muscles, muscle rigidity, profuse sweating, diarrhea, headache, shivering, and Goosebumps. Severe serotonin syndrome can be life-threatening. Signs include high fever, seizures, irregular arrhythmia, and coma. Tramadol is one of the numerous drugs and abuse substances which possibly implicated in serotonin syndrome [5]. The wavy triple electrocardiographic sign (Yasser’s Sign) is a recently innovative diagnostic sign in hypocalcemia [6]. The analysis for this sign in the author's interpretations is based on the following; 1. Different successive three beats in the same lead are affected. 2. All ECG leads can be implicated. 3. An associated elevated beat is seen with the first of the successive three beats, a depressing beat with the second beat, and an isoelectric ST-segment in the third one. 4. The elevated beat is either accompanied by ST-segment elevation or just an elevated beat above the isoelectric line. 5. Also, the depressed beat is either associated with ST-segment depression or just a depressing beat below the isoelectric line. 6. The configuration for depressions, elevations, and isoelectricities of the ST segment for the subsequent three beats are variable from case to case. So, this arrangement is non-conditional. 7. Mostly, there is no participation among the involved leads. The author intended that is not conditionally included in the special coronary artery for the affected leads [6].  Coronary artery spasms (CASs) are suggested pathogenesis for induced myocardial infarction [4]. CS is a strong vasoconstriction of coronary arteries that causes total or partial artery blockage [7]. CAS has a pivotal role in the pathogenesis of ischemic heart disease, including stable angina, unstable angina, MI, and sudden cardiac death (SCD) [8]. Approximately, hypertension and hypercholesterolemia are the most common causes of CAS [9]. Smoking is a major risk factor for CAS [10].

Aim of this study: In this manuscript, I reported a case of acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, the Wavy triple sign (Yasser’s sign), and serotonin syndrome after an overdose of oral tramadol in a middle-aged male patient.

A 53-year-old, Carpenter, heavy smoker, married, male Egyptian patient was presented to the emergency department (ED) with fever, tachypnea, severe angina chest pain, and palpitations. Profuse sweating and severe headaches were the associated symptoms. He gave a recent history of taking 250 mg of oral tramadol tablets as a single dose to improve his mood within 3 hours. The patient appears distressed, anxious, irritable, tachypneic, has profuse sweating, and has central cyanosis. His vital signs were as follows: an irregular heart rate of 93 bpm, blood pressure of 190/130 mmHg, respiratory rate of 32 bpm, a temperature of 39 °C, and pulse oximeter of oxygen (O2) saturation of 90%. GCS was 15. Generalized coarse crepitations were on the chest auscultation. No more relevant clinical data were noted during the clinical examination. He was initially managed in the ED with O2 inhalation using a nasal mask at the rate of 5 L/min, and IV boluses of frusemide (3 ampoules of 40mg injection; total; 120 mg). Initial ECG tracing was done in the ED showing sinus arrhythmia (VR; 93) and ST-segment elevations in aVL, V1, V2, and V3 leads, and both down-slopping and up-slopping ST-segment depressions in II, III, and aVF leads. There is a Wavy triple sign (Yasser’s sign) of hypocalcemia in V4 and V5 leads. There is evidence of widespread AC artifacts and loose V6 lead (Figure 1). The patient was admitted to the intensive care unit (ICU) admission and was initially treated with O2 inhalation (100%, by nasal cannula, 10L/min) by oxygen central flow system and sublingual isosorbide dinitrate (5 mg; single dose). The second ECG tracing was done within 18 minutes of the initial tracing and on the ICU admission showing sinus tachycardia (VR;100) and ST-segments elevations in aVL, V1, V2, and V3 leads, and both down-slopping and up-slopping ST-segments depressions in II, III, and aVF leads. There are horizontal (V5) and down-slopping ST-segment depressions (V6) leads. There is evidence of both tremor and AC artifacts (Figure 2A). Unfortunately, ventricular fibrillation (VF; Figure 2B) and death had happened before being given aspocid, clopidogrel, and streptokinase rather than completing the remaining essential treatment. Cardiopulmonary resuscitation (CPR) was done according to the current international guidelines. But the SCD was the end. The initial workup lab was; Immediate ABG was (PH; 7.47 mmHg, PCO2; 33 mmHg, HCO3; 24 mmHg, SO2; 93%, and PaO2; 78 mmHg). The random blood sugar was 206 mg /dl, WBCs were 17,000. SGPT was; 44 U/L, SGOT was; 40 U/L, serum creatinine (0.7 mg/dl), blood urea (22 mg/dl), and serum ionized calcium (0.83 mmol/L). The troponin test was positive (4.3 ng/L). There is no more workup and radiological imaging. Tramadol induces acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, Wavy triple sign (Yasser’s sign), and serotonin syndrome was the most probable provisional diagnosis.

Figure 1: An initial ECG tracing was done on the presentation in the ED showing sinus arrhythmia (VR;93 ) and ST-segments elevations in aVL, V1, V2, and V3 leads (red arrows), and both down-slopping and up-slopping ST-segments depressions in II, III, and aVF leads (lime arrows). There is a Wavy triple sign (Yasser’s sign) of hypocalcemia in V4 and V5 leads (green, orange, and dark blue arrows).  Small yellow arrows indicate AC artifacts. A large pink arrow indicates loose V6 lead.

Figure 2: A- The second ECG tracing was done within 18 minutes of the initial tracing and on the ICU admission showing sinus tachycardia (VR;100) and ST-segments elevations in aVL, V1, V2, and V3 leads (red arrows), and both down-slopping and up-slopping ST-segments depressions in II, III, and aVF leads (lime arrows). There are horizontal (V5) and down-slopping ST-segment depressions (V6) leads (lime arrows). Small dark blue arrows indicate both tremor and AC artifacts. Figure 2 B- ECG tracing was done within 9 minutes of the last tracing in the ICU and just before cardiac arrest showed ventricular fibrillation.

Overview:

A middle-aged, Carpenter, heavy smoker, married, male patient presented to the ED with acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, Wavy triple sign (Yasser’s sign), and serotonin syndrome after an overdose of oral tramadol. The primary objective for my case study was the presence of a patient with acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, and serotonin syndrome after an overdose of oral tramadol in ED. The secondary objective for my case study was the question of; how you manage the case at the ICU.  After the exclusion of other possible triggers in the current case, Naranjo's probability scale was used to evaluate the association between tramadol ingestion and the development of acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, Wavy triple sign (Yasser’s sign), and serotonin syndrome. Naranjo's probability scale in the current case study was +8. This means that there was a probable relationship between these adverse drug reactions and tramadol ingestion. (Table 1).

Table 1: Naranjo Algorithm-Adverse Drug Reaction (ADR) Probability Scale in the case report.

• In the current case, there are acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, Wavy triple sign (Yasser’s sign), and serotonin syndrome post-overdose of oral tramadol had happened.
• Serotonin syndrome and coronary artery spasms were possible interpretations for most of symptoms after tramadol toxicity.
• Smoking was a main risk factor [10]. The increasing dose of tramadol was another major risk factor.
• Acute respiratory distress syndrome due to COVID-19 pneumonia was the possible differential diagnosis for the current case study.
• It is recommended to widen the research in clearing the effect of tramadol in inducing- acute anteroseptal myocardial infarction, hypertensive crises, pulmonary edema, Wavy triple sign (Yasser’s sign), and serotonin syndrome.
• I can’t compare the current case with similar conditions. There are no similar or known cases with the same management for near comparison.
• The only limitation of the current case study was the SCD.

The association of overdose of oral tramadol with acute myocardial infarction, hypertensive crises, pulmonary edema, and the Wavy triple sign (Yasser’s sign) is tremendous.

• Tramadol overdose may be lethal.
• The constellation of acute myocardial infarction, hypertensive crises, pulmonary edema, ECG sinus tachycardia, hypoxia, and Wavy triple sign (Yasser’s sign) of hypocalcemia, cigarette smoking may carry poor prognostic factors and progress step for sudden cardiac death.
• The priority of management for any physician should be directed to identifying the etiology and knowing the drug's adverse effects.

There are no conflicts of interest.

Acknowledgment

I wish to thank the team of critical care nurses and the emergency department at Faraskor Central Hospital who made extra ECG copies to help me. Also, I want to thank my wife for saving time and improving the conditions for supporting me.

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