key: cord-1029763-43aijg6x authors: Raad, Mohamad; Gorgis, Sarah; Dabbagh, Mohammed; Chehab, Omar; Parikh, Sachin; Singh, Gurjit title: Right Heart Strain on Presenting 12-Lead Electrocardiogram Predicts Critical Illness in COVID-19 date: 2020-09-18 journal: JACC Clin Electrophysiol DOI: 10.1016/j.jacep.2020.09.013 sha: 83856bb34086dd74b8bcecad624f87efa3eddc15 doc_id: 1029763 cord_uid: 43aijg6x Background Cardiovascular comorbidities and complications, including right ventricular dysfunction, are common and are associated with worse outcomes in patients with COVID-19. The data on the clinical utility of 12-lead electrocardiograms (ECG) to aid with prognosis is limited. Objectives We aim to assess the association of new right heart strain patterns on presenting 12-lead electrocardiogram (RHS-ECG) with outcomes in patients hospitalized with COVID-19. Methods We retrospectively evaluated records from 480 patients who were consecutively admitted with COVID-19. ECGs obtained at the time of presentation in the emergency department (ED) were considered as index ECGs. RHS-ECG was defined by any new right axis deviation, S1Q3T3 pattern, or ST depressions with T-wave inversions in leads V1-3 or II, III, aVF. Multivariable logistic regression was performed to assess whether RHS-ECG is independently associated with our primary outcomes. Results ECGs from the ED were available for 314 patients who were included in the analysis. Most patients were in sinus rhythm, with sinus tachycardia being the most frequent dysrhythmia. RHS-ECG findings were present in 40 (11%) patients. RHS-ECG was significantly associated with the incidence of adverse outcomes and an independent predictor of mortality (adjOR, 15.2 (95% [CI, 5.1-45.2]; P<0.001), the need for mechanical ventilation (adjOR, 8.8 [95% CI, 3.4-23.2]; P<0.001), and their composite (adjOR, 12.1 [95% CI, 4.3-33.9]; P<0.001). Conclusions RHS-ECG was associated with mechanical ventilation and mortality in patients admitted with COVID-19. Special attention should be taken in patients admitted with new signs of RHS on presenting ECG Several risk factors have been reported to be associated with COVID-19 severity and outcomes. Emerging information has revealed that cardiovascular complications, including right ventricular dysfunction and cor pulmonale, are common and confer worse outcomes in patients admitted with COVID-19 (2, 3) . Clinical tools such as troponin levels, 12-lead electrocardiograms (ECG), and echocardiograms are being used to aid with diagnosis and prognosis, although there is limited information due to lack of data. This study aimed to describe the characteristics and outcomes of patients admitted with COVID-19 in a tertiary referral center emergency department (ED) and to assess whether new right heart strain patterns on presenting ECG (RHS-ECG) were associated with specific outcomes. Demographics, vital signs, comorbid conditions, laboratory, and radiologic data at hospital admission were manually collected from the electronic health records (Table 1 and Supplementary Table 1 ). Symptoms were deemed positive if endorsed within 24 hours of presentation. Baseline results refer to initial blood samples collected in the ED or the first values within 24 hours of admission. Comorbid conditions were identified based on admission diagnoses. ECGs from the ED were read by G.S. and S.P., who were blinded to data and outcomes. ECG signs suggestive of RHS were defined by any of the following: new right axis deviation, S 1 Q 3 T 3 pattern, or ST Depressions with T-wave inversions in leads V 1-3 and II, III, aVF not present on prior ECG. Cardiac injury on 12-lead electrocardiogram was defined by any ST elevation, depression, or T-wave flattening or inversion that were not due to repolarization abnormalities. Cardiac injury via laboratory data was defined by a high sensitivity troponin level > 99th percentile (4,5) (>18 ng/L in our assay). The degree of hypoxia was measured as the ratio of peripheral capillary oxygen saturation (SpO 2 ) to the fraction of inspired oxygen (FiO 2 ), SPO 2 : FiO 2, in accordance with the original mSOFA investigations (6) . SpO 2 values were obtained from pulse oximetry ED vital logs or arterial blood gases. For those who were not intubated, FiO 2 was J o u r n a l P r e -p r o o f estimated by multiplying liter flow per minute by 0.03 and adding that to 0.21, in accordance with original mSOFA investigations (6) . The primary outcomes were mortality, need for mechanical ventilation, and their composite. The secondary outcomes were acute kidney injury (AKI), need for renal replacement therapy, acute respiratory distress syndrome (ARDS), and different composites of the mentioned outcomes. ARDS was defined according to the Berlin definition (7) and AKI was defined according to the "Kidney Disease: Improving Global Outcomes" criteria for creatinine (8) . The cohort was categorized based on the presence of RHS-ECG (Table 1 ) and the primary outcomes (Supplementary Table 1 ). The clinical data elements of different groups were compared using Chi-Square (χ2) test for categorical variables and analysis of variance or Kruskal-Wallis test for continuous variables based on the normality of the data. Univariate analysis was first done to identify the significant variables associated with the designed primary outcome. Multivariable logistic regression analysis was then performed to identify significant predictors of that outcome. Candidate variables for model inclusion included statistically and clinically relevant variables associated with COVID-19 critical illness (9,10) and those with a P-value ≤0.05 on univariable analysis for our primary outcomes. The model exit criteria P-value ≥0.1. Almost all patients were in sinus rhythm, with sinus tachycardia being the most frequent dysrhythmia. The mean age was 60 ± 14 years, and 151 (48%) were women. There were 34 (11%) patients with new RHS-ECG that were not present on prior ECGs. Presence of ECG signs of Right Heart Strain There were several differences between patients with RHS-ECG and those without. Patients with RHS-ECG were older and statistically more likely to have a history of cerebrovascular disease, chronic obstructive pulmonary disease, and be smokers (all P<0.05). These patients were also more likely to have risk factors for cardiovascular disease (diabetes mellitus, coronary artery disease, chronic kidney disease), however the difference did not reach statistical significance (table 1) . Baseline laboratory data, including inflammatory markers, were compared between both groups. Upon admission, patients with RHS-ECG had higher D-dimer levels (1.12 vs. 0.78 µg/mL, P=0.009), but there were no differences in baseline lactate dehydrogenase and ferritin levels ( Table 1) . Patients with RHS-ECG were more likely to have an elevated brain natriuretic peptide level in addition to cardiac injury as defined by a troponin level > 99 th percentile. There was no statistical difference in chest imaging findings (Table 1) . Among the 40 patients who had new ECG patterns suggestive of RHS, there were 17 (54%) new right axis deviation, 13 (38%) S 1 Q 3 T 3 pattern, or 11 (32%) ST depressions with Twave inversions in leads V 1-3 or II, III, aVF that were not present on prior ECG. In addition, 10 (29%) patients had an early R/S transition within the anterior chest leads. Please see Table 3 for the different combinations observed. Table 1 . Patients who were intubated were more likely to be male, and those who were deceased were more likely to be older (Supplementary Table 1 ). Patients who were intubated or died had a lower SPO 2 :FiO 2 ratio in the ED (Supplementary Table 1 ) and were more likely to have ECG findings suggestive of RHS (Supplementary Table 1 ). Patients who required mechanical ventilation were more likely to have atrial fibrillation on ECG. Patients who were intubated or died were more likely to have a higher number of comorbidities, including heart failure, atrial fibrillation, cerebrovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and be smokers (Supplementary Table 1 ). They were also more likely to have higher high sensitivity troponin levels, lactate dehydrogenase, ferritin, and D-dimer levels. There was also no difference in chest imaging findings between the different outcome groups (Supplementary Table 1 ). Patients with RHS-ECG were significantly more likely to be intubated, discharged deceased, or their composite, as outlined in the multivariable analysis section below ( Figure 1 , (Table 2c ). In this study, we describe the characteristics and outcomes of patients hospitalized with COVID-19 according to RHS-ECG on the presenting ECG obtained in the ED. This study J o u r n a l P r e -p r o o f reveals that RHS-ECG is associated with a higher risk of worse outcomes, including mortality, mechanical ventilation, acute kidney injury, renal replacement therapy, and ARDS. Cardiovascular comorbidities have been shown to be associated with a higher risk of morbidity and mortality in patients admitted with COVID- 19 (11,12) . Several studies have also revealed that cardiac injury, as evidenced by an elevated troponin, is associated with worse outcomes, including ARDS and mortality (4) . The link between the mechanism of cardiac injury associated with COVID-19 and worse outcomes is not well elucidated. In our study, we observed an association between RHS-ECG and cardiac injury, both of which were independent predictors of worse outcomes in patients admitted with COVID-19. It is difficult to assess direct causation, especially since these ECG signs are suggestive of RV strain and were mostly not supported by further evaluation. However, a few speculations may be drawn. In our study, 3/4 of echocardiograms performed on patients with RHS-ECG revealed findings consistent with RV dysfunction. Published studies and case series have shown that RV dysfunction appears to be the predominant cardiac pathology on inpatient echocardiograms performed (13) . The mechanism of RV dysfunction could be due to multiple factors. Respiratory failure is the most common cause of death in patients admitted with COVID-19. Hypoxic vasoconstriction or physical destruction of the capillary beds leading to elevated pulmonary vascular resistance is one proposed mechanisms of RV dysfunction. Interestingly, RHS-ECG continued to be an independent predictor of the need for mechanical ventilation or mortality, even after factoring in the degree of hypoxia using the SPO 2 :FiO 2 ratios. Patients admitted with COVID-19 also have an increased prevalence of venous thromboembolism (14- with RHS precede asystole/pulseless electrical activity arrest from hypoxic respiratory failure (19) . It is also possible that patients with RHS-ECG in our cohort represented those who present later in the course of their COVID-19 illness. This is further evidence that RV dysfunction is an end-stage complication prior to adverse events. Among available clinical tools, ECGs are easily performed, cost-effective, and widely available. The detection of ECG-RHS provides a simple and powerful tool with early discriminatory ability, as early as presentation to the ED. That said, only 314/480 (65%) of patients in our cohort had an ECG obtained in the ED with even lower rates in a prior published cohort from Wuhan (4). We suggest obtaining a baseline ECG for all patients admitted with COVID-19 as identification of RHS-ECG may guide early triage and management of these patients. The main limitation of our study is its retrospective design. Despite controlling for multiple variables, there may be confounding variables that are not accounted for. The patient population chosen included those who were admitted and cannot be generalized to all patients with COVID-19. Furthermore, patients were excluded if they were still admitted at the time of data collection and analysis as our primary outcome could not be accurately assessed. Most J o u r n a l P r e -p r o o f importantly, while ECG findings suggestive of RHS conferred worse outcomes, the data available do not allow correlation with echocardiographic findings, nor do they allow a complete assessment of possible etiologies (example pulmonary emboli). Larger prospective studies will be required to validate and better characterize our results in relationship to echocardiographic evidence of RV strain in addition to potential mechanisms such as pulmonary embolism. The temporality of RHS-ECG patterns cannot be ascertained entirely despite being new as compared to prior ECGs present. Therefore, these findings may have been present prior to admission and not related to COVID-19. However, these findings still beneficial for risk prediction as our results reveal an early discriminatory ability of RHS-ECG when obtained as early as in the ED. Prospective trials will help address this limitation in addition to any benefit in serial risk prediction with serial inpatient ECG or telemetry monitoring to assess whether the evolution/resolution of RHS-ECG confers different inpatient risks. The presence of RHS-ECG is associated with an increased risk of critical illness in SARS-CoV-2 is a highly contagious and virulent pathogen. In areas of high case density where resource allocation is desperately needed, cost-effective, and easily performed tests, which can risk-stratify patients are invaluable. In our study, the detection of new right heart strain patterns on the presenting ECG predicted critical illness in patients admitted with COVID-19. This can potentially facilitate early triage and management of COVID-19 patients presenting to the ER with RV strain. Additionally, this finding highlights the role of right ventricular dysfunction in the pathophysiology of COVID-19. Translational Outlook: Validation of our findings in a larger prospective patient population provides a novel prognostic marker that can be used in prediction models to facilitate appropriate patient triage and resource allocation. Table 1 . Clinical characteristics of patients according to the presence or absence of signs of right heart strain on the presenting 12-lead electrocardiogram Legend: Age is expressed as a mean ± standard deviation whereas all other continuous variables are expressed as medians (interquartile ranges) * Cardiac Injury as defined by a troponin level above the 99th percentile (>18 ng/L) † Elevated Brain Natriuretic Peptide as defined by a level above the 50 pg/L Coronavirus COVID-19 Global Cases by the Cardiovascular comorbidities, cardiac injury and prognosis of COVID-19 in Acute Cor Pulmonale in Critically Ill Patients with Covid-19 Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Cardiac Injury Patterns and Inpatient Outcomes Among Patients Admitted with COVID-19 A modified sequential organ failure assessment score for critical care triage Acute respiratory distress syndrome: the Berlin Definition Clinical Practice Guideline for Acute Kidney Injury Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China The Spectrum of Cardiac Manifestations in Coronavirus Disease 2019 (COVID-19) -a Systematic Echocardiographic Study Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis Autopsy Findings and Venous Thromboembolism in Patients With COVID-19 High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19 Cardiovascular complications in COVID-19 Electrocardiographic right ventricular strain precedes hypoxic pulseless electrical activity cardiac arrests: Looking beyond pulmonary embolism The authors thank Karla D Passalacqua, PhD, at Henry Ford Hospital, for assistance with editing. Age is expressed as a mean ± standard deviation whereas all other continuous variables are expressed as medians