HISTORY, CURRENT ILLNESS AND PHYSICAL EXAMINATION
PERSONAL HISTORY
42-year-old woman from Venezuela. Resident in Spain since February 2018.
Last trip to her country of origin: June 2018.
No family history of heart disease or sudden death.
No known drug reactions.
No classic cardiovascular risk factors (CVRF) or toxic habits.
Subclinical hypothyroidism.
Repeated tonsillitis in childhood.
Fibrocystic mastopathy with bilateral partial mastectomy in 2016.
G2A0P0C2. Two healthy children.
No chronic home treatment.

CURRENT DISEASE
At the beginning of February 2019, the patient came to the emergency department of our centre with a 4-day history of continuous, oppressive, non-radiating central thoracic pain, with no associated vegetative cortex, which worsens with decubitus and deep inspiration and improves with sitting and leaning forward. In addition, he reported a parallel decrease in the rate of diuresis. Prior to this, he had a non-productive cough for 3 days, generalised arthromyalgia, a feeling of dystrophy and intense asthenia. He denies orthopnoea, episodes of paroxysmal nocturnal dyspnoea, bendopnoea, increased abdominal or lower limb circumference, weight gain, palpitations or other cardiovascular symptoms. Denies abdominal pain, nausea, vomiting, diarrhoea, micturition symptoms or other infectious organ focality.

PHYSICAL EXAMINATION
Blood pressure (BP) 87/59 mmHg, heart rate (HR) 100 bpm. Temperature: 36.1 ̊C. SpO2 100% basal.
Regular general condition. Conscious, oriented in the 3 spheres and cooperative.
Normal colour, normohydrated and normoperfused. Eupneic at rest, with good respiratory dynamics.
Head and neck: oropharynx normal. No jugular venous engorgement.
Cardiac auscultation: rhythmic, tachycardic heart sounds. No murmurs or extratonos.
Pulmonary auscultation: preserved vesicular murmur, no extra sounds.
Abdomen: hydro-aerial sounds present and of normal characteristics. Soft, depressible, not painful on palpation. No signs of peritoneal irritation or ascitic semiology. No masses or organomegaly palpable.
Lower extremities: pedial pulses present and symmetrical. No oedema or signs of deep vein thrombosis.

COMPLEMENTARY TESTS
Emergency ECG: sinus rhythm at 88 bpm, vertical cardiac axis, normal PR, narrow QRS, low voltages. Poor R wave growth in precordial leads. No relevant repolarisation alterations.
Chest X-ray in the ED: Cardiothoracic index at the upper limit of normality (this is an anteroposterior projection). The costophrenic sinuses are free.
No parenchymal infiltrates or parenchymal consolidations were observed, nor was there any evidence of frank pulmonary congestion.
Laboratory tests in the emergency department:
Venous blood gases: anion GAP 10, pH 7.29. pCO2 47 mmHg, pO2 6 mmHg. HCO3 23 mmol/l. BEb -4.2 mmol/l. sO2 18 %. Na+ 135 mEq/l. K+ 4.5 mEq/l. Cl- 107 mEq/l.
Ca+2 1,11 mmol/l. Glucose 152 mg/dl. Lactate 4.2 mmol/l. Oxyhaemoglobin 18%.
Carboxyhaemoglobin 0%. Methaemoglobin 1%. Reduced haemoglobin 81%.
Haemoglobin 13.4 g/dl. sO2(c) 4.
Biochemistry: glucose 153 mg/dl. Creatinine 0.58 mg/dl. Sodium 141 mEq/l. Total protein 6 g/dl. Potassium 4,75 mEq/l. Albumin 3.1 g/dl. Chlorine 102 mEq/l. ALT (GPT) 11 U/l. AST (GOT) 29 U/l. Gamma-GT 7 U/l. Alkaline phosphatase 41 U/l. LDH 326 U/l. Bilirubin 0.2 mg/dl. Calcium 8 mg/dl. Magnesium 1.72 mg/d. C-reactive protein 0.76 mg/dl. Urea 23 mg/dl.
Haemogram: red blood cells 5.02 x mill/μl. Haemoglobin 13.3 g/dl. Haematocrit 41.5 %.
MCH 26.5 pg. MCV 82.6 fl. MCCH 32.1 g/dl. RDW 15%. Platelets 235.000/μl. MPV 8.6 fl. Leukocytes 9,600/μl. Neutrophils 8,100/μl. Neutrophils % 84.1 %. Lymphocytes 900/μl. Lymphocytes % 9.1 %. Monocytes 600/μl. Monocytes % 6.4 %. Eosinophils 0/μl.
Eosinophils % 0.1 per cent. Basophils 0/μl. Basophils % 0.3%.
Coagulation: prothrombin time 12.9 s. Prothrombin activity 82%. Prothrombin activity 82%. INR 1.12. TTPa 29 s. Fibrinogen 280 mg/dl. D-dimer 461 ng/ml.
Markers of myocardial damage: CK 218 U/l. Troponin T hs 295.3 ng/l (normal < 14 ng/l).
NT-proBNP 7,836 pg/ml.
Microbiology: PCR for respiratory viruses in nasopharyngeal exudate positive for influenza A, subtyping: H1N1.
Urgent transthoracic echocardiogram: non-dilated left ventricle with global hypokinesia. LVEF 25-30%. Non-dilated right ventricle with normal EF. Mild mitral insufficiency. Thin film of effusion (0.5-1 mm) around the right chambers and inferolateral to the left ventricle. Inferior vena cava not dilated, adequate respiratory variation.
Transthoracic echocardiogram on admission to the coronary unit: study performed in sinus tachycardia at 120 bpm. Left ventricle not dilated, slightly hypertrophic. Systolic function severely depressed (LVEF 28% by Simpson biplane) due to global hypokinesia. Normal diastolic function. Non-dilated right ventricle with depressed systolic function (TAPSE: 10 mm, S-wave: 8.5 cm/s, FAC: 25%), subjective mild moderate dysfunction with global hypokinesia. Normal sized left atrium.
Right atrium of normal size. Trivalve aortic valve, morphologically and functionally normal. Mitral valve with mild insufficiency. Tricuspid valve morphologically normal, with slight insufficiency that does not allow estimation of PSAP. No indirect signs of pulmonary hypertension. Inferior vena cava not dilated with collapse > 50% with inspiration. Aortic root, ascending aorta and aortic arch of normal size.
Slight pericardial effusion without haemodynamic compromise.
Transthoracic echocardiogram during ECMO weaning: systolic function preserved throughout the study. No changes in biventricular size and function with ECMO flow reduction (up to 0.5 l/min). Study performed in sinus tachycardia at 105 bpm. Left ventricle not dilated, with normal wall thickness. Segmental contractility with mild hypokinesia of inferior aspect and septum. Myocardial thickness 10-11 mm. Preserved systolic function (LVEF 55% by Simpson biplane, improvement with respect to the study of 48h ago). Diastolic function with E=A, diastolic predominance in pulmonary vein flow, normal E/E'. Right ventricle not dilated (basal DTD 31 mm) with normal systolic function. Atria of normal size. Aortic valve morphologically and functionally normal. Mitral valve with slight thickening of the anterior leaflet, mild/trivial insufficiency. Tricuspid valve morphologically normal, with moderate II/IV insufficiency allowing estimation of PSAP of 29 mmHg + DBP. Aortic root of normal size. Pericardium of normal thickness and refractoriness, without effusion.
Cardiac magnetic resonance (CMR) (images 3-9, videos 8 and 9): left ventricle not dilated or hypertrophic, normal global and segmental systolic function (LVEF 56%).
Non-dilated right ventricle with normal systolic function (LVEF 60%). No alterations in segmental contractility. Atria not dilated. Morphologically and functionally normal valves. No pericardial abnormalities. Late enhancement sequences show areas of faint diffuse intramyocardial uptake with no distribution corresponding to any coronary territory. This corresponds to the presence of signal hyperintensity on the STIR sequence. These data suggest the presence of oedema and inflammatory changes. Extracardiac findings: consolidation in the left lower lobe and atelectasis/subsegmental infiltrates in the right lower lobe.
Conclusion: LV and RV with normal global and segmental systolic function. Signs of oedema and inflammatory changes in the LV with diffuse distribution compatible with the clinical diagnosis of myocarditis.
Pathological anatomy of endomyocardial biopsy: histological sections of the submitted sample correspond to fragments of endomyocardial tissue that do not show endocardial lesions and show myocardium without architectural loss, with no granulomas or giant cells or neutrophilic or lymphocytic inflammatory infiltrates. There are no signs of vasculitis. No malignancy is noted.

CLINICAL COURSE
Initially, given the hypotension observed in the emergency department, intensive serum therapy was started with little response. Given the patient's symptoms and blood tests, the emergency department requested cardiology assessment, who performed an urgent transthoracic echocardiogram, which revealed severe left ventricular dysfunction with global hypokinesia, as well as a thin layer of pericardial effusion that did not produce echocardiographic involvement of the cavities. Given the clinical and analytical data of haemodynamic instability (hypotension that did not respond to serum therapy, progressive distal hypoperfusion, hyperlactacidemia), it was decided to admit him to the coronary unit for monitoring and initiation of vasoactive drugs. Also, given the previous clinical manifestations of upper respiratory tract infection, a nasopharyngeal swab was requested for respiratory viruses (positive for influenza A virus) and empirical antimicrobial therapy was started with oseltamivir, ceftriaxone and levofloxacin, the latter to cover possible bacterial superinfection.
In the coronary unit, vasopressor support was started with noradrenaline at increasing doses and inotropic support with dobutamine, despite which the patient persisted with mean BP around 65 mmHg. Invasive haemodynamic monitoring by Swan-Ganz catheter showed the following initial parameters: cardiac index around 2 l/min/m2, PAPm 17 mmHg, PCP 15 mmHg, mixed venous saturation 50%. A new transthoracic echocardiogram was also performed, confirming the findings of the previous one, with a biplane Simpson LVEF of 28%, and also showing at least moderate right ventricular dysfunction with global hypokinesia and mild mitral insufficiency.
During the following 24 hours, the patient showed a poor clinical and analytical response (NT-proBNP of 18,528 pg/ml at this time) to the treatment given, with progressive worsening of haemodynamic parameters (lactic acid 6.5 mmol/l, cardiac index in decline, oliguria) despite support with dobutamine at 13 mcg/kg/min and noradrenaline at 0.35 mcg/kg/min, so it was decided to implant an intra-aortic balloon counterpulsation device. During the balloon implantation, he presented an episode of severe hypotension with a drop in cardiac index to 1.5, requiring a significant increase in vasopressor support, with noradrenaline infusion of up to 2 mcg/kg/min, despite which lactic acid levels rose to 9.5. In this context, it was decided to contact cardiac surgery for urgent implantation of veno-arterial ECMO (Cardiohelp system), which was performed at the bedside without the need for orotracheal intubation (awake ECMO implantation), and the patient was transferred to the cardiac ICU for continuity of care.
During her stay in the cardiac ICU, there was a progressive improvement in haemodynamic parameters that allowed early withdrawal of noradrenaline. A few hours later, he began to show symptoms compatible with acute ischaemia of the right lower limb, and the femoral artery was cannulated for distal perfusion, which had not been possible at first due to the urgency of the cannulation. An endomyocardial biopsy was also performed, with no peri- or post-procedural complications and no pathological findings. After 3 days of ECMO support, the echocardiogram showed recovery of ventricular function, so weaning was attempted under echocardiographic control. In this context, the patient presented congestive symptoms with desaturation and worsening respiratory mechanics, without simultaneous ventricular dysfunction on echocardiography, but with a possible component of diastolic dysfunction, so it was decided not to withdraw assistance. Chest X-ray and lung ultrasound showed a large left pleural effusion, which was drained by thoracentesis, obtaining about 1,000 ml of serous fluid. A levosimendan infusion was also started, which was well tolerated from the haemodynamic point of view, and after 10 days of support, ECMO was withdrawn. In this context, he presented with significant bleeding with secondary instability, requiring polytransfusion and reinitiation of vasoactive support, but with a good evolution that also allowed the removal of the counterpulsation balloon.
Once respiratory and haemodynamic stability was achieved, she was discharged to the conventional cardiology hospital ward, where she remained asymptomatic at all times, with no arrhythmic or other events during her stay. Cardiac magnetic resonance imaging was performed, showing data compatible with myocarditis, as well as preserved biventricular function, and cardiac and functional rehabilitation was started with good learning and clear improvement. The only sequelae of the patient was a slight limitation to dorsiflexion of the right foot.
After 21 days of total hospitalisation and being practically in her baseline condition, she was discharged home with subsequent review in cardiology consultations.

DIAGNOSIS
Cardiogenic shock with need for ECMO V-A implantation secondary to fulminant myocarditis due to influenza A.
Transient severe LV systolic dysfunction in the context of the above.
Viral upper respiratory tract infection due to influenza A.
Partial acute respiratory failure secondary to all of the above.
Acute right lower limb ischaemia after ECMO V-A cannulation, resolved.
