key: cord-0893524-r2bqqovo
authors: Qian, Hao; Gao, Peng; Tian, Ran; Yang, Xufei; Guo, Fan; Li, Taisheng; Liu, Zhengyin; Wang, Jinglan; Zhou, Xiang; Qin, Yan; Chang, Long; Song, Yanjun; Yan, Xiaowei; Wu, Wei; Zhang, Shuyang
title: Myocardial Injury on Admission as a Risk in Critically Ill COVID-19 Patients: a Retrospective in-ICU Study
date: 2020-10-16
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2020.10.019
sha: 1ad5203e2c25007ce3560494bd379331685f6457
doc_id: 893524
cord_uid: r2bqqovo

OBJECTIVE: The aim of this study was to investigate the incidence, clinical presentation, cardiovascular (CV) complications and mortality risk of myocardial injury on admission in critically ill ICU inpatients with COVID-19. DESIGN: A single-center, retrospective, observational study. SETTING: A new-built ICU in Tongji hospital (Sino-French new city campus), Huazhong University of Science and Technology, Wuhan, China. PARTICIPANTS: Seventy-seven critical COVID-19 patients. INTERVENTIONS: Patients were divided into myocardial injury group and non-myocardial injury group according to the on-admission levels of high-sensitivity cardiac troponin I. MEASUREMENTS AND MAIN RESULTS: Demographic data, clinical characteristics, laboratory tests, treatment and clinical outcome were evaluated stratified by the presence of myocardial injury on admission. Compared with non-myocardial injury patients, patients with myocardial injury were older (68.4 ± 10.1 vs. 62.1 ± 13.5 years; P=0.02), had higher prevalence of underlying CV disease (34.1% vs. 11.1%; P=0.02) and in-ICU CV complications (41.5% vs13.9%; P=0.008), higher Acute Physiology and Chronic Health Evaluation II scores (20.3 ± 7.3 vs 14.4 ± 7.4; P=0.001) and Sequential Organ Failure Assessment scores [7, interquartile range (IQR) 5-10 vs. 5,IQR 3-6; P<0.001]. Myocardial injury on admission increased the risk of 28-day mortality [hazard ratio (HR), 2.200; 95% confidence interval (CI) 1.29 to 3.74; P=0.004]. Age ≥ 75 years was another risk factor for mortality (HR, 2.882; 95% CI 1.51 to 5.50; P=0.002). CONCLUSION: Critically ill patients with COVID-19 held high risk of CV complications. Myocardial injury on admission may be a common comorbidity and is associated with severity and a high risk of mortality in this population.

The outbreak of novel coronavirus disease (COVID-19) caused by SARS-Cov-2 has now become a global health emergency. 1, 2 COVID-19-related pneumonia and acute respiratory distress syndrome (ARDS) are the major causes of hospital admission in most patients. However, cardiovascular (CV) complications including myocardial injury and arrhythmia have been reported in recent literature. [3] [4] [5] [6] [7] The specific incidence of myocardial injury and its association with the mortality in patients with COVID-19 have been widely demonstrated. [8] [9] [10] However, investigations focusing on the incidence and mortality risk of myocardial injury in critically ill in-intensive care unit (ICU) patients with COVID-19 are still limited.

Therefore, a need exists to characterize CV complications and myocardial injury because an increasing number of countries are facing the difficult situation of a vast number of critically ill patients and increasing cases of CV complications that China encountered from Jan. to Apr. 2020. We conducted a retrospective study of data from 77 patients admitted to a newly constructed ICU in Wuhan, compared patients with and without myocardial injury, detailed the relationship of myocardial injury with the survival rate and CV outcomes, and presented the following conclusions: 1) Myocardial injury is a common complication in critically ill COVID-19 patients; 2)

Patients with myocardial injury are more likely to develop adverse events and fatal outcomes during hospitalization; 3) Myocardial injury and advanced age (≥75 years old) are independent risk factors for 28-day in-ICU mortality.

This single-center, retrospective, observational study enrolled patients admitted to a newly constructed ICU in Tongji Hospital (Sino-French New City Campus), Huazhong University of Science and Technology, Wuhan, China. "Newly constructed"

indicates that the quarantine ICU was equipped and modified from a previous general ward within 3 days and designated to treat critically ill COVID-19 patients. The ICU was staffed with a multidisciplinary team including 185 health care providers from Peking Union Medical College (PUMC) Hospital, Beijing, China. Because of the emergency nature of the situation, this ICU lacked sufficient equipment, such as invasive hemodynamic monitors, at the beginning of operation. We retrospectively analyzed patients who were admitted to the ICU from Feb. 4 to Mar. 3, 2020. The confirmation of novel coronavirus infection was defined as a positive result of a throat-swab specimen on a real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. The cutoff of data for investigation of survival status was Mar. 19, 2020. Patients were followed up at least 28 days or died before the cut-off date. The study was approved by Ethical Committee of PUMC Hospital.

The data analyzed in this study were extracted from electronic medical records and included demographics and baseline characteristics (i.e., pre-existing CV diseases

[CVD] and CV risk factors), clinical information (i.e., vital signs and therapeutic management), laboratory results and outcomes. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were determined on the date of ICU admission. The time from symptom onset to ICU admission, intubation and death were also recorded. Patients were categorized into two groups, including those with or without myocardial injury (myocardial injury and non-myocardial injury group) on admission according to troponin test results on the first day in the ICU. Covariates of interests were compared between these two groups.

Myocardial injury was defined as an elevated cardiac troponin value above the 99th percentile upper reference limit (URL) according to the Fourth Universal Definition of Myocardial Infarction. 11 A high-sensitivity cardiac troponin I (hs-cTnI)assay was implemented in this study, and the 99th URL was 28 ng/L. Prior CVD included a prior medical history of coronary artery disease (CAD), myocardial infarction, heart failure and stroke. CV death was defined as a death caused directly by CV complications, such as cardiogenic shock, and occurrence of sudden cardiac arrest and/or fatal ventricular arrhythmia in relatively stable patients. CV complications included in-ICU cardiac arrest, cardiac shock, acute myocardial infarction, atrial fibrillation and malignant ventricular arrhythmia. ARDS and acute kidney injury were diagnosed according to the Berlin Definition and Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines, respectively. 11, 12 We defined liver abnormalities as any parameter greater than the upper limit of the normal values of alanine aminotransferase (ALT) and total bilirubin (TBIL).

Vasoconstrictive support was mostly applied in patients with shock status (combined with blood pressure lower than 90/60 mmHg or evidence of insufficient perfusion). The V-V mode of extracorporeal membrane oxygenation (ECMO) was used in these patients and was mainly performed to improve oxygen supply and attenuate severe hypercarbia under mechanical ventilation.

In the further analysis of risk factors for mortality, we conducted a survival study based on age (≥75 and <75 years old), prior CVD history and myocardial injury on admission. The primary endpoint was 28-day mortality after ICU admission, and the secondary outcome was CV death.

Continuous variables are presented as the mean ± standard deviation (SD) for those with a normal distribution or the median and inter-quartile range (IQR) for those with a non-normal distribution. Categorical variables are described by the number (%).

Two-sample T test and Mann-Whitney U test were applied to assess the differences in continuous variables between patients with and without myocardial injury. The differences in categorical variables were assessed using χ² test and Fisher's exact test (for small sample sizes). Survival analyses were based on the time from ICU admission to the event. Kaplan-Meier plots and Cox proportional hazards regression models were used to assess survival data. Statistical significance was determined by a two-sided α value less than 0.05. All statistical analyses were performed using the SPSS 21.0 software (IBM, Armonk, NY). Table 1 . Compared to the non-myocardial injury group, patients with myocardial injury were significantly older (68.4 ± 10.1 years vs. 62.1 ± 13.5 years; P=0.022), had more concurrent CVD (34.1% vs. 11.1%; P=0.017), including CAD (19.6% vs. 2.8%; P=0.032), and were more likely to be smokers (53.6% vs. 22.2%; P<0.01). However, the prevalence rates of other CVDs, such as myocardial infarction, heart failure and stroke, or other CV risk factors, such as hypertension and diabetes, were not significantly different.

As summarized in Table 2 , there was no significant difference in vital signs (heart rate, respiratory rate and blood pressure) between the two groups on ICU admission.

When two important indices for assessing and predicting ICU performance and ICU mortality, the APACHE II and SOFA scoring systems, were compared, the myocardial injury group had significantly higher scores than the non-myocardial injury group (APACHE II: 20.3 ± 7.3 vs. 14.4 ± 7.4, P<0.01; SOFA: 7 IQR 5-10 vs. 5 IQR 3-6, P<0.01, respectively). When complications were considered, a significant difference in CV complications (41.5% vs. 13.9%; P<0.01) was observed between the two groups ( Table 2 ). Most patients (75 of 77, 97.4%) had ARDS on admission, and there was no significant difference in acute kidney injury or liver dysfunction between the two groups.

The admission laboratory findings revealed that patients with myocardial injury had a significantly lower platelet count, longer prothrombin time (PT), higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and D-dimer levels, and reduced renal function according to higher serum creatinine and blood urea nitrogen (BUN) levels compared to the non-myocardial injury patients (Table 3 ). There was no significant difference in life support therapy, including in-ICU oxygen therapy, intubation rate, vasoconstrictive agents and blood purification therapy, between the groups. Similar in-ICU usage of antiviral and/or antibacterial agents, immunoglobulin and glucocorticoids was observed. The only significant difference in therapy was that more non-myocardial injury patients received anticoagulation therapy than myocardial injury patients (69.4% vs. 39.0%, P<0.01) ( Table 2) .

When survival outcomes were summarized, 58 (75.3%) patients had died within 28 days of ICU admission, including 6 (7.8%) patients who died from CV causes. As indicated in Table 1 , the patients with myocardial injury had significantly higher rates of all-cause death and CV death than non-myocardial injury patients (85.3% vs.

63.9%, P=0.029 and 14.6% vs. 0%, P=0.027, respectively). Although the durations from symptom onset to ICU admission and intubation were similar in these two groups, the duration from symptom onset to death in patients with myocardial injury was significantly shorter than that of non-myocardial injury patients (27.8 ± 14.2 vs.

38.5 ± 15.7 days, P=0.022).

We conducted Cox regression analyses to compare survival between patients ≥75 years and those <75 years, with or without admission myocardial injury and pre-existing CVD. Adjusted variates included smoking history, creatinine levels greater than 104 μmol/L (normal limitation), D-dimer levels greater than 13.5 mg/L (median level) and NT-proBNP levels greater than 852 ng/L (median level). The older patients had a higher risk of all-cause death (HR, 2.882; 95% CI 1.51 to 5.50; P=0.002) than patients <75 years (Figure 2a) . Consistently, the in-ICU cumulative survival curve of myocardial injury patients was significantly lower than that of non-myocardial injury patients (HR, 2.200; 95% CI 1.29 to 3.74; P=0.004) ( Figure   2b ). However, no significant difference was observed in survival between patients with or without pre-existing CVD (HR, 1.396; 95% CI 0.74 to 2.64; P=0.31) ( Figure   2c ).

In this study, we report 77 critically ill patients with confirmed novel coronavirus Elevated hs-cTnI or myocardial injury is well-recognized as a primary complication contributing to increased respiratory syndrome severity and total mortality in patients infected with COVID-19, 13-16 especially in critically ill patients. 17 Several studies have indicated that myocardial injury occurrence was a predictor for disease progression, as more than 80% of myocardial injury patients infected with novel coronavirus developed critical illness. 3, 6 This speculation was documented by our study, as the APCHE II and SOFA scores of the myocardial injury patients were significantly higher than those of patients without myocardial injury. Additionally, we further compared the mortality and time from ICU admission to death between the myocardial injury and non-myocardial injury patients, which suggested the predictive value of co-existing myocardial injury on admission as a high-risk factor in critically ill patients with COVID-19 in this study. However, serum troponin level elevation should be carefully interpreted by specialized physicians because of its high sensitivity. Various non-cardiovascular factors, such as fever with rapid heart rate, electrolyte disorder and kidney dysfunction, may contribute to troponin level elevation. 18, 19 In critical patients, myocardial injury results from various clinical mechanisms that may include severe hypoxia, insufficient perfusion, systemic inflammation and coagulation dysfunctions. [18] [19] [20] There was no evidence of acute coronary syndrome or coronary artery-related CV events as the major cause of elevated troponin based on electrocardiography and echocardiography findings. In our patients, severe hypoxia was suggested as the major cause of myocardial injury, as most had rapid progression of dyspnea with an oxygenation index (PaO 2 /FiO 2 ) <200, and more than 95% (including all myocardial injury patients) developed ARDS. Moreover, although 18 patients were intubated and sedated before being sent to the ICU, the mean baseline respiratory rate still exceeded 28 times per minute, suggesting the wide occurrence of dyspnea in our patients. Additionally, 14 patients received vasoconstrictive agents on the first day of admission, indicating a prevalence of shock or insufficient peripheral perfusion. The imbalance of increased cardiac metabolic demand and decreased blood perfusion/oxygen supply may contribute to myocardial injury and dysfunction. 21 A high prevalence of coagulation disequilibrium was also closely observed in our patients, especially in those with myocardial injury (higher D-dimer levels and longer PT). Anti-coagulation therapies such as low molecular weight heparin or unfractionated heparin were empirically prescribed. These therapies seemed to be effective for restoring coagulation abnormalities and coagulopathy, which might potentially benefit the prognosis. Additionally, a high systemic inflammatory burden was demonstrated to be positively associated with myocardial injury in critically ill patients with COVID-19. 22 In this study, anti-inflammation therapies such as glucocorticoids or tocilizumab were used in some patients, and we found that inflammatory cytokine levels were decreased. However, related clinical investigations were not performed in this study. Concrete clinical values for anti-coagulation and anti-inflammation therapies in critical patients with COVID-19 should be explored in further studies.

Age and pre-existing CVD have been associated with higher mortality in critically ill patients with viral infection. Older patients may have more comorbidities (i.e., CAD, hypertension, chronic kidney disease and diabetes) and a higher rate of CV complications. In fact, no patients over 80 years had survived at the end of this study. However, this does not mean that young adults will not develop critical illness. The youngest patient in our ICU with invasive mechanical ventilation was 26 years, and two more patients in their thirties were admitted. The youngest death was 47 years old in our study. Our study verified that COVID-19 patients with myocardial injury had a higher prevalence of prior CVD. No significant difference in survival rate was noted between patients with or without pre-existing CVD. We suspect that the extremely high mortality might partially conceal the contribution of previous CVD to death. Thus, our study cannot exclude the risk of pre-existing CVD in mildly or moderately ill patients with COVID-19 (patients with respiratory symptoms [fever, cough, etc.] and/or manifestations of pneumonia in imaging examinations). In our study, the prevalence of pre-existing CVD in patients with myocardial injury was higher than that in patients without myocardial injury, but the prevalence of myocardial injury in patients with prior CVD was not explored.

Whether pre-existing CVD increases the incidence of myocardial injury in COVID-19 patients requires further investigation.

There is no direct evidence indicating that COVID-19-related viral myocarditis is a major cause of myocardial injury and death in this study. In our previous echocardiography study, although several presentations of cardiac dysfunction (e.g., pericardial effusion, increased left ventricular [LV]) mass index, decreased LV stroke volume index and impaired right ventricle systolic function) were general features of critical patients, LV systolic dysfunction (such as decreased LV ejection fraction [LVEF] or newly diagnosed abnormal ventricular wall movement) was not common. 26 There were only four cases of reduced LVEF, including two related to prior myocardial infarction/ischemia, one patient with hypothermia and one patient with unconfirmed dilated cardiomyopathy. As for the electrocardiography presentations, sinus tachycardia, atrial fibrillation, ventricular tachyarrhythmias and non-specific ST-T changes were commonly found in these patients, but no indications for fulminant COVID-19-related myocarditis were found. We do not have cardiac magnetic resonance images because this procedure was not applicable for these quarantined critically ill patients. Therefore, viral myocarditis was also not presented in pathology studies. In a report of three autopsies of COVID-19 patients, no pathological findings indicated viral myocarditis, and the nucleic acid tests for the 2019 novel coronavirus were negative in heart tissue, although mild infiltration of lymphocytes, monocytes and neutrophils and necrosis of cardiomyocytes were observed. 27 Similar results were also reported by Xu et al., who found that novel coronavirus infection might not directly impair the heart tissue in another autopsy report, as they found a few interstitial mononuclear inflammatory infiltrates without other substantial damage in the myocardial tissue. 28 We have close communication with the pathologists and are expecting further results of autopsies including several of our patients. 29 The prevalence of admission myocardial injury was considered as an increased risk of 28-day mortality in our study, but it was not likely to be the cause of death. We considered hs-cTnI elevation on admission as a biomarker of risk. We carefully investigated the six patients with cardiovascular death, and they all had myocardial injury. Two patients with prior myocardial infarction (without revascularization) had sudden cardiac death, which were considered as coronary thrombosis events. Two cases of fatal ventricular fibrillation were reexamined and found to have underlying hypokalemia during urgent intubation or deep vein catheterization. One cardiac arrest was related to hyperkalemia (7.2 mmol/L). Only one patient had troponin elevation, cardiac shock without evidence of sepsis or respiratory failure, significantly reduced LVEF and four chamber enlargements; however, we did not exclude the prior history of dilated cardiomyopathy.

This study focused on critically ill patients with COVID-19 and found that myocardial injury was a common complication and indicative of a poor prognosis in these patients. Furthermore, advanced age was also positively associated with high mortality. Regarding the pathogenesis, the critical status of multi-organ failure or high systemic inflammatory burden may partially explain the onset of myocardial injury.

Evidence for viral myocarditis is currently lacking. It is necessary to pay increased attention to myocardial injury during treatment of critically ill patients with COVID-19. 

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* Non-normal distribution. ALT, alanine aminotransferase; BUN, blood urea nitrogen; hsCRP, high-sensitivity C-reactive protein

INR, international normalized ratio; hs-cTnI: high-sensitivity cardiac troponin I; NT-proBNP: N-terminal pro-B-type natriuretic peptide. P values present the differences between myocardial injury and non-myocardial injury patients