1

Introduction

Takotsubo cardiomyopathy (TTC) is a transient condition that affects the myocardium and is seen mostly in post-menopausal women secondary to an emotional or physical stressor; however, certain drugs have been described as cause of this syndrome. Patients with TTC usually present with shortness of breath and chest pain and usually have total recovery of the cardiac function, necessitating only supportive care. However, cardiac arrest or refractory cardiogenic shock could be the initial presentation of this condition, and more aggressive and invasive interventions might be required. We report the case of a young female with medication-induced TTC, who presented with cardiogenic shock as initial manifestation. She was treated successfully with extracorporeal membrane oxygenation (ECMO). To our knowledge, this is the first case in the literature describing the use of ECMO in cardiogenic shock due to drug-induced TTC.

2

Case presentation

A 31 year-old Hispanic female presented to the emergency department (ED) for altered mental status and hypotension one hour after taking a bottle of ibuprofen combined with diphenhydramine. She was not on any medication and had no allergies or significant family history. Prior to this event the patient was completely healthy. At admission her blood pressure was 90/54 mmHg, heart rate 98 beats per minute, respiratory rate 20/minute, oxygen saturation 90 percent on room air. On physical examination, the patient was obtunded, heart sounds were regular with no murmurs or gallops. On lung examination there were bilateral crackles. An initial electrocardiogram (ECG) showed sinus rhythm at 78 beats per minute, first degree AV block and intraventricular conduction delay (IVCD). Additionally, there was a transient Brugada-like ST-elevation in V2 ( Fig. 1 ). Twenty minutes after arrival, the patient went into cardiac arrest due to pulseless electrical activity (PEA), with return of spontaneous circulation (ROSC) within 10 minutes of cardiopulmonary resuscitation (CPR). She was started on inotropes and mechanical ventilation with fraction of inspired oxygen (FiO2) of 1.0. In the next hour, the patient had two other episodes of cardiac arrest due to PEA and ventricular tachycardia, respectively, with ROSC within 10 minutes on both occasions. At this point, the patient was on maximal doses of epinephrine and norepinephrine. A repeat ECG showed sinus tachycardia at 110 beats/minute and a prolonged corrected QT interval (QTc) ( Fig. 2 ).

EKG on admission showing sinus tachycardia, intraventricular conduction delay and Brugada like ST elevation in lead V2.

Repeat EKG showing sinus tachycardia and a corrected QT interval of 499 ms.

An echocardiogram showed ejection fraction of 20% and extensive akinesia of mid and apical segments with hyperdynamic base, consistent with TTC ( Videos 1a, 1b ). Arterial blood gases showed PH: 7.18, PCO2 57 mmHg, PO2 69 mmHg, HCO3 22 MMO/L, lactic acid of 6.3 MMO/L. Blood chemistry, complete blood count, acetaminophen and salicylate level were all normal. Cardiac enzymes were not consistent with an acute coronary syndrome (highest troponin 1.2 ng/ml and CK-MB 3.9 ng/ml after CPR). An X-ray of the chest showed pulmonary edema ( Fig. 3 ).

CXR showing pulmonary edema.

Due to persistent hemodynamic instability from refractory cardiogenic shock, evidenced by blood pressure of 85/40 mmHg and heart rate of 110 beats per minute, on maximal doses of two inotropes and oxygen saturation of 60 percent, therapy with extracorporeal membrane oxygenation (ECMO) was considered as a lifesaving alternative. The cardiothoracic (CT) surgery service proceeded with emergent implantation of ECMO therapy in the ED. The right axillary artery and left femoral veins were cannulated and an arterio-venous ECMO was implanted. The vital parameters stabilized right after implantation of ECMO; inotropes were weaned off and discontinued within the next 3 hours; the blood pressure remained stable. Blood gases after four hours of ECMO therapy showed PH: 7.43, PO2 371 mmHg, PCO2 26 mmHg, HCO3 17 MMOL/L and lactic acid 7.5 MMOL/L.

Thirty six hours post initiation of ECMO therapy an echocardiogram showed improvement of the systolic function, with ejection fraction of 40% and improvement of pulmonary edema on chest X ray. ECG showed sinus rhythm at 88 beats/minute with deep inverted T waves in precordial and limb leads and prolonged QTc ( Fig. 4 ). The decision was made to start weaning off the ECMO. The device was fully explanted within the next 12 hours; vital signs and arterial blood gases remained stable. Next day, the patient was liberated from the mechanical ventilation. Chest X-ray showed significant improvement of pulmonary edema. The patient was transferred to a regular floor two days later. A repeat echocardiogram showed ejection fraction of 60% with no evidence of wall motion abnormality ( Videos 2a, 2b ); repeat EKG showed normal QTc and diffuse precordial T wave inversions. The patient was transferred to the psychiatry unit on hospital day eight.

EKG showing sinus rhythm, deep inverted T waves in precordial leads and corrected QT interval of 630 ms.

3

Discussion

Takotsubo cardiomyopathy (TTC) or transient left ventricular apical ballooning syndrome (TLVAS), as it is also referred to, is a relatively new entity in the medical literature, initially described in 5 patients in Japan in 1990 by Dote et al. . The condition is characterized by transient left ventricular dysfunction, depicted by akinesia or dyskinesia of the apex, along with mid ventricular dysfunction and normal to hyperkinetic basal segments . The electrocardiogram in patients with TTC can show ST segment elevations, which can be accompanied or not by T wave inversions . ST segment elevations can evolve to inverted T waves and QT prolongation . In our case, the patient did not present with ST segment elevations. However, she did develop subsequent T wave inversions and QT prolongation. Moreover, cardiac enzymes could be elevated in these patients . The diagnosis of acute coronary syndrome (ACS) has to be considered in these patients, for which a coronary angiogram is warranted in most individuals with suspicion of having TTC, according to the diagnostic Mayo clinic diagnostic criteria. A coronary angiogram was not performed in our case, due to lack of risk factors for coronary artery disease, absence of chest pain at presentation, no ST segment elevations, no serial rise in cardiac biomarkers typical for ACS (highest cardiac troponin was 1.2 ng/ml and CK-MB 3.9 ng/ml), and, in retrospective, the recovery of the left ventricular systolic function in less than 48 hours without any coronary intervention, did not suggest ACS.

There have been several mechanisms described to explain the pathophysiology of TTC. However, the one proposing myocardial dysfunction, caused by catecholamine surge secondary to emotional or physical stress, seems to be the most convincing . This theory goes along with findings of Wittstein et al. showing that the catecholamine levels are increased in patients with TTC when compared to those with actual myocardial infarction . Other suggested mechanisms are, coronary artery vasospasm and microvascular dysfunction . Additionally, there have been case reports associating cephalosporins, analgesics and withdrawal from beta blockers with the syndrome . In a review by Pedro Amariles, 20 drugs were identified as possible causes of TTC. These included vasoactive drugs, antidepressants, chemotherapeutics, potassium chloride and levothyroxine .

A systematic review including 286 patients showed that TTC is mostly seen in postmenopausal women. In the same study the condition comprised 2 percent of those initially diagnosed with ST-segment elevation myocardial infarction. Moreover, in 26 percent of patients an emotional stress had preceded the initiation of the symptoms, and a physical stress did the same in 37 percent of cases. The most common presentation was chest pain and dyspnea (67 percent) . In contrast, our patient was a young, non-menopausal woman who presented with hypotension and altered mental status with progression to cardiac arrest. There have been case reports of TTC in which in the initial presentation was cardiac arrest . However, very few cases of medication-induced TTC have been reported presenting with cardiogenic shock.

Treatment of such patients represents a real challenge, given the lack of guidelines addressing management of TTC. Usually, patients presenting with TTC and no complications can be managed with supportive therapy until the myocardium recovers . When the initial presentation of TTC is cardiac arrest or refractory heart failure, use of vasoactive drugs to maintain blood pressure and adequate tissue perfusion seems to be the most logical option. However, given the presumptive role of catecholamines in the pathophysiology of the syndrome , use of vasopressors might have more deleterious results than possible benefits. Worsening of hemodynamics in our patient might have been partly due to the use of vasopressors. It is in this situation when the use of mechanical circulatory support can be lifesaving. Some authors have used with success the intra-aortic balloon pump . In our case, the patient was in frank hemodynamic collapse and also was not oxygenating well. Therefore, the decision was made to start treatment with ECMO in an attempt to tide over the acute phase and at the same time provide hemodynamic and respiratory support, which also helped in weaning the vasopressors fast.

In order to initiate ECMO therapy, a vessel (usually a vein) has to be cannulated to withdraw blood from the body. Right after, the blood goes to an external oxygenator, which also removes carbon dioxide, then, the blood is returned to the body through a vein or an artery . There are three modalities of vascular access depending on patients’ needs. Veno-venous cannulation is mostly used for respiratory support, while veno-arterial access, aside of providing respiratory support, also gives hemodynamic support . The latter modality was the one used in our patient. Ideally, the common femoral artery and femoral vein are the preferred access sites for veno-arterial ECMO. But in our patient, the femoral artery was barely palpable, and due to her small body habitus and severe vasoconstriction as a result of high dose vasopressors, successful cannulation and usability of the femoral artery were doubtful. Hence, we opted for axillary artery cut down for arterial access, and femoral vein was used for venous access.

The ECMO therapy has emerged as a lifesaving therapeutic option for patients with cardiac arrest and refractory cardiogenic shock. Patients who benefit the most are those with reversible cardiac dysfunction, in whom the device functions as a bridge to recovery; providing hemodynamic support until the underlying problem resolves. Bonacchi et al. reported the case of a patient who presented with TTC, with subsequent development of refractory cardiogenic shock. The patient was successfully managed with extracorporeal life support . Similarly, other two cases of TTC secondary to cesarean section, were managed successfully with ECMO therapy . Unlike the aforementioned cases, our patient went into cardiac arrest, and the ECMO had to be implanted in the ED, in order to prevent an otherwise unavoidable demise. Other authors have reported the use of ECMO therapy in the emergency department for cases of cardiac arrest and cardiogenic shock . However, no case report has been published describing ECMO being used for management of cardiac arrest due to TTC.

The prognosis of patients with TTC is usually very good . Among the complications that can arise, heart failure and pulmonary edema are the most common . In a systematic review done by Bybee and colleagues, the following complications of TTC were found: cardiogenic shock, ventricular arrhythmias, heart failure, dynamic intraventricular obstruction, mitral regurgitation, left ventricular free-wall rupture and left ventricular thrombus formation . In addition, cardiac tamponade has also been reported as a possible complication . The 4 year recurrence rate of TTC in one series was 11.4 percent .