Title: Ventricular Fibrillation Storm in Coronavirus 2019
Abstract: Cardiac arrhythmia is a known manifestation of novel coronavirus 2019 (COVID-19) infection. Herein, we describe the clinical course of an otherwise healthy patient who experienced persistent ventricular tachycardia and fibrillation which is believed to be directly related to inflammation, as opposed to acute myocardial injury or medications that can prolong the QT interval. Cardiac arrhythmia is a known manifestation of novel coronavirus 2019 (COVID-19) infection. Herein, we describe the clinical course of an otherwise healthy patient who experienced persistent ventricular tachycardia and fibrillation which is believed to be directly related to inflammation, as opposed to acute myocardial injury or medications that can prolong the QT interval. In addition to acute respiratory complications, coronavirus disease 2019 (COVID-19) also causes significant consequences for the cardiovascular system, particularly arrhythmia.1World Health Organization. Coronavirus Disease (COVID-19) Situation Reports. Available at:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200404-sitrep-75-covid-19.pdf?sfvrsn=99251b2b_2. Accessed on June 5, 2020.Google Scholar,2Driggin E Madhavan MV Bikdeli B Chuich T Laracy J Biondi-Zoccai G Brown TS Der Nigoghossian C Zidar DA Haythe J Brodie D Beckman JA Kirtane AJ Stone GW Krumholz HM Parikh SA Cardiovascular Considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1454) Google Scholar Due to the panoply of precipitating factors that can cause cardiac arrhythmia in COVID-19 patients, identifying the underlying culprit is crucial for proper management. Herein, we describe the course of a COVID-19 patient who experienced an electrical storm of ventricular fibrillation (VF). A 55-year-old woman with history significant for ischemic cerebral vascular infarction (6 years prior) presented with expressive aphasia and stroke-like symptoms. Computed tomography head scan ruled out acute cerebral stroke. Vital signs, laboratory data, and electrocardiogram are in Table 1. Urine analysis was positive for bacteriuria. At screening, she tested positive for COVID-19. At that time she was not complaining of any constitutional or respiratory symptoms. She was admitted for cerebral vascular stroke workup and was started on intravenous ceftriaxone for urinary tract infection. Following admission, she became severely hypotensive and experienced worsening leukocytosis and renal function, causing concern for septic shock. Further laboratory workup revealed high interleuken 6 (16.4 pg/ml, upper limit normal = 1.8 pg/ml). She was transferred to the intensive care unit, where circulatory support and corticosteroids were initiated. She experienced sinus bradycardia with a heart rate of 40 beats per minute and was subsequently started on a dopamine infusion. Later that day, she went into cardiac arrest due to Torsades de Pointe (TdP) (Figure 1). A 200 joules shock was delivered, the patient regained sinus rhythm, and was subsequently intubated; her QTc interval was 535 ms. A lidocaine infusion and aggressive empiric magnesium supplementation were initiated. Although receiving dopamine and lidocaine infusions, she remained bradycardic and experienced another VF and TdP cardiac arrest requiring defibrillation; transcutaneous pacing was started. Convalescent serum was administered as her inflammatory markers continued to rise along with worsening circulatory and respiratory failure. Despite dopamine, lidocaine, and transcutaneous pacing, she had multiple VF arrests requiring more than 60 defibrillator shocks. Her echocardiogram revealed normal left ventricular wall motion with normal function. Serial troponin levels were assessed, peaking at 0.064 ng/ml. At that point, the family signed comfort care only, the patient was extubated, and infusions stopped. Miraculously, she dramatically improved, with QTc improving from > 700 ms to 500 ms. The repeat echocardiogram did not reveal significant changes. The patient was never treated with hydroxychloroquine or azithromycin. She did not have any additional arrhythmias for the duration of her hospital stay. QTc interval returned to baseline. She had a full recovery and was discharged home on a life vest with plans for outpatient genetic tests for QTc prolongation. On a 4-week follow-up, her EKG showed normal QRS/QTc and she felt great without palpitations, syncope, or life vest shocks.Table 1Vital signs, laboratory data and electrocardiogram parametersTime of ObservationVariablePresentationVentricular FibrillationDischargeBlood pressure (mm Hg)112/6995/5098/63Heart rate (beats per minute)9440–5080–90Temperature (Fahrenheit)99.798.198Respiratory rate (breaths per minute)16–2028–2816–18Oxygen saturation (%)999798Sodium (meq/L)133143136Potassium (meq/L)3.13.23.9Magnesium (meq/L)2.01.51.8Serum creatinine (mg/dl)1.50.670.74Aspartate transaminase (H/L)1073370Alanine transaminase (U/L)742680Alkaline phosphatase (U/L)1229978Total bilirubin (mg/dl)0.90.30.3Troponins (ng/ml)<0.012<0.012<0.012D-dimer (mg/L FEU)211410C-reactive protein (mg/dl)>205.41.3Interleukin-6 (pg/ml)-16.4-Lactate dehydrogenase (U/L)324496220Ferritin (ng/ml)872>100640White blood cell count (10*3/uL)18.73710Hemoglobin (g/dl)11.51111.5Platelet (K/uL)240528407International normalized ratio1.1-1.2P-R interval (ms)150168150QRS duration (ms)728062QTc interval (ms)427650467 Open table in a new tab One study reported ventricular tachycardia/VF in 5.9% (11/187) of COVID-19 patients (Table 23Guo T Fan Y Chen M Wu X Zhang L He T Wang H Wan J Wang X Lu Z Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-8Crossref Scopus (2886) Google Scholar, 4Goyal P Choi JJ Pinheiro LC Schenck EJ Chen R Jabri A Satlin MJ Campion Jr, TR Nahid M Ringel JB Hoffman KL Alshak MN Li HA Wehmeyer GT Rajan M Reshetnyak E Hupert N Horn EM Martinez FJ Gulick RM Safford MM Clinical characteristics of Covid-19 in New York City.N Engl J Med. 2020; 382: 2372-2374Crossref PubMed Scopus (1597) Google Scholar, 5Kochav SM Coromilas E Nalbandian A Ranard LS Gupta A Chung MK Gopinathannair R Biviano AB Garan H Wan EY Cardiac arrhythmias in COVID-19 infection.Circ Arrhythm Electrophysiol. 2020; 13e008719Crossref PubMed Scopus (93) Google Scholar, 6Chorin E Wadhwani L Magnani S Dai M Shulman E Nadeau-Routhier C Knotts R Bar-Cohen R Kogan E Barbhaiya C Aizer A Holmes D Bernstein S Spinelli M Park DS Stefano C Chinitz LA Jankelson L QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.Heart Rhythm. 2020; (S1547-5271(20)30435)Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 7Shao F Xu S Ma X Xu Z Lyu J Ng M Cui H Yu C Zhang Q Sun P Tang Z In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, China.Resuscitation. 2020; 151: 18-23Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 8Bhatla A Mayer MM Adusumalli S Hyman MC Oh E Tierney A Moss J Chahal AA Anesi G Denduluri S Domenico CM Arkles J Abella BS Bullinga JR Callans DJ Dixit S Epstein AE Frankel DS Garcia FC Kumareswaram R Nazarian S Riley MP Santangeli P Schaller RD Supple GE Lin D Marchlinski F Deo R COVID-19 and cardiac arrhythmias.Heart Rhythm. 2020; (S1547-5271(20)30594)Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 9Mitacchione G Schiavone M Gasperetti A Forleo GB Ventricular tachycardia storm management in a COVID-19 patient: a case report.Eur Heart J - Case Rep. 2020; ytaa217: 1-6Google Scholar), with elevated troponin-T increasing risk, suggesting that myocardial injury precipitates arrhythmia.2Driggin E Madhavan MV Bikdeli B Chuich T Laracy J Biondi-Zoccai G Brown TS Der Nigoghossian C Zidar DA Haythe J Brodie D Beckman JA Kirtane AJ Stone GW Krumholz HM Parikh SA Cardiovascular Considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1454) Google Scholar However, ventricular tachycardia/VF also occurs in patients with low troponin, suggesting alternative causes, such as QTc prolonging medication (e.g., hydroxychloroquine).2Driggin E Madhavan MV Bikdeli B Chuich T Laracy J Biondi-Zoccai G Brown TS Der Nigoghossian C Zidar DA Haythe J Brodie D Beckman JA Kirtane AJ Stone GW Krumholz HM Parikh SA Cardiovascular Considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1454) Google Scholar Another possibility is the fulminant systemic inflammatory state in sick patients with cardiovascular morbidities and metabolic disarray. Inflammatory cardiac channelopathies, induced by inflammatory markers, can prolong the action potential and cause long QT syndrome and TdP.10Lazzerini PE Capecchi PL Laghi-Pasini F Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis.Eur Heart J. 2017; 38: 1717-1727PubMed Google Scholar,11Lazzerini PE Laghi-Pasini F Boutjdir M Capecchi PL Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies.Nat Rev Immunol. 2019; 19: 63-64Crossref PubMed Scopus (96) Google Scholar Moreover, systemic inflammation can increase risk for ventricular arrhythmia indirectly by inducing a hyper-sympathetic state or inhibiting cytochrome p450.11Lazzerini PE Laghi-Pasini F Boutjdir M Capecchi PL Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies.Nat Rev Immunol. 2019; 19: 63-64Crossref PubMed Scopus (96) Google Scholar Other inflammatory responses, such as fever, can trigger undiagnosed conduction diseases or channelopathies, like Brugada syndrome.12Chang D Saleh M Garcia-Bengo Y Choi E Epstein L Willner J COVID-19 infection unmasking brugada syndrome.HeartRhythm Case Rep. 2020; 6: 237-240Abstract Full Text Full Text PDF PubMed Scopus (59) Google ScholarTable 2Articles describing arrhythmic events in patients with COVID-19Number of Patients with Event of InterestFirst AuthorDateSample SizeVentricular TachycardiaElevated TroponinsVentricular Tachycardia/Fibrillation Cardiac ArrestVentricular Tachycardia StormGuoMarch 2020n = 187119—-—-GoyalApril 2020n = 3931—-—-—-KochavMay 2020n = 11*The patient had prolonged QTc, heart failure with preserved ejection fraction, diabetes mellitus, and atrial fibrillation.111ChorinMay 2020n = 2511†The patient was in Torsades de Pointe and on hydroxychloroquine + azithromycin.—-—-1ShaoJune 2020n = 7618—-—-—-BhatlaJune 2020n = 70010—-1—-MitacchioneJuly 2020n = 11‡The patient had heart failure with reduced ejection fraction and coronary artery disease.—-—-1 The patient had prolonged QTc, heart failure with preserved ejection fraction, diabetes mellitus, and atrial fibrillation.† The patient was in Torsades de Pointe and on hydroxychloroquine + azithromycin.‡ The patient had heart failure with reduced ejection fraction and coronary artery disease. Open table in a new tab Reducing this inflammatory state in COVID-19 patients can mitigate arrhythmic events, as well as other morbidity and mortality. Tocilizumab, an anti-interleuken 6 receptor monoclonal-antibody, yielded a survival benefit in COVID-19 patients.13Coyle J Igbinomwanhia E Sanchez-Nadales A Danciu S Chu C Shah N A recovered case of COVID-19 myocarditis and ARDS treated with corticosteroids, tocilizumab, and experimental AT-001 [published online ahead of print, 2020 May 3].JACC Case Rep. 2020; https://doi.org/10.1016/j.jaccas.2020.04.025Crossref PubMed Google Scholar, 14Lazzerini PE Boutjdir M Capecchi PL COVID-19, arrhythmic risk, and inflammation: mind the gap!.Circulation. 2020; 142: 7-9Crossref PubMed Scopus (184) Google Scholar, 15Xu X Han M Li T Sun W Wang D Fu B Zhou Y Zheng X Yang Y Li X Zhang X Pan A Wei H Effective treatment of severe COVID-19 patients with tocilizumab.Proc Natl Acad Sci U S A. 2020; 117: 10970-10975Crossref PubMed Scopus (1806) Google Scholar Tocilizumab was shown to have a robust shortening of the QTc prolongation induced by abundant inflammatory cytokines in patients with acute rheumatoid arthritis.16Lazzerini PE Acampa M Capecchi PL Fineschi I Selvi E Moscadelli V Zimbone S Gentile D Galeazzi M Laghi-Pasini F Antiarrhythmic potential of anticytokine therapy in rheumatoid arthritis: tocilizumab reduces corrected QT interval by controlling systemic inflammation.Arthritis Care Res (Hoboken). 2015; 67: 332-339Crossref PubMed Scopus (86) Google Scholar Additionally, preliminary reports from ongoing trials indicate toclizumab may reduce adverse myocardial injury in acute inflammatory cardiac injury.2Driggin E Madhavan MV Bikdeli B Chuich T Laracy J Biondi-Zoccai G Brown TS Der Nigoghossian C Zidar DA Haythe J Brodie D Beckman JA Kirtane AJ Stone GW Krumholz HM Parikh SA Cardiovascular Considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1454) Google Scholar,13Coyle J Igbinomwanhia E Sanchez-Nadales A Danciu S Chu C Shah N A recovered case of COVID-19 myocarditis and ARDS treated with corticosteroids, tocilizumab, and experimental AT-001 [published online ahead of print, 2020 May 3].JACC Case Rep. 2020; https://doi.org/10.1016/j.jaccas.2020.04.025Crossref PubMed Google Scholar The initial hypothesis regarding our patient's VF storm etiology was acute myocarditis; however, with consistently normal troponins, the explanation is likely a constellation of factors, including hypokalemia, hypomagnesemia, bradycardia and long QTc, in the setting of hyper-inflammation (Figure 2). This hypothesis is supported by significantly elevated inflammatory markers. As such, this report suggests that the hyper-inflammatory state in COVID-19 patients can induce ventricular arrhythmias, which may cease abruptly following a reduction in inflammation, in our case from convalescent serum and/or hydrocortisone therapy.17Yang SS Lipes J Corticosteroids for critically ill COVID-19 patients with cytokine release syndrome: a limited case series.Can J Anaesth. 2020; 11: 1-3Google Scholar,18Man SF Sin DD Effects of corticosteroids on systemic inflammation in chronic obstructive pulmonary disease.Proc Am Thorac Soc. 2005; 2: 78-82Crossref PubMed Scopus (51) Google Scholar Hence, dampening this fulminant inflammatory condition may prevent or decrease cardiac arrhythmias.