The main findings of this study are that (1) cardiac dysfunction commonly occurs in critical illness caused by COVID-19; (2) RV dysfunction, defined as a TAPSE < 17 mm or moderately to severely depressed function assessed visually, was associated with an increased risk of death; (3) cardiac dysfunction is not easily recognized by clinical variables; and that (4) cardiac biomarkers have a moderate value in detecting cardiac dysfunction in patients critically ill with COVID-19.
We found that 32% of the patients had LV or RV dysfunction at some time during their stay in the ICU. Cardiac dysfunction was more common at the time of admission to the ICU than later in the ICU-period. The incidence of cardiac dysfunction was in line with other studies of patients hospitalized, whose COVID-19 disease severities ranged from mild to severe, and where LV dysfunction was found in 10 to 42% and RV dysfunction in 14 to 39% [15, 23, 24]. One reason for the relatively low incidence of RV dysfunction may have been the liberal use of thromboprophylaxis that was introduced early in the study period [25], leading to less pulmonary embolism than in many earlier studies [15, 26]. We did not assess patients with tissue doppler or strain analysis, modalities that are more sensitive for the detection of ventricular dysfunction, which could explain a comparative low incidence of cardiac dysfunction in our study.
We found a number of different types of LV dysfunction. Two patients had suspected COVID-19 myocarditis; the diagnosis was verified in one patient. Knowledge of COVID-19 myocarditis is still very limited. Patients are reported to present in various ways and they may have either global or regional hypokinesia, with or without preserved ejection fraction, and their recovery time may be brief or prolonged [27, 28]. There are no strict criteria for COVID-19 myocarditis. In the present study we can neither confirm nor exclude additional cases within our cohort. Five patients presented with a clinical presentation of the Takotsubo syndrome. Severe respiratory distress is an established trigger of Takotsubo, and the incidence we found is in agreement with other studies of Takotsubo syndrome in critically ill patients [29]. Moreover, Takotsubo has also been reported in several case studies of patients with COVID-19 [11, 12]. One patient was diagnosed with PIMS-TS, a condition associated with cardiac dysfunction in COVID-19 [30]. Other plausible causes of LV dysfunction are secondary effects due to hypoxia, hypotension, or a toxic effect due to the inflammatory state [31]. RV dysfunction was seen in 18% of participants, and there was a close correlation between elevated PAP and RV dysfunction. Thus, RV dysfunction in most cases is probably attributable to an increased RV afterload. Elevated PAP was common in our study population, having been seen in nearly one-third of all patients. Both pulmonary embolism and pulmonary microangiopathy with microthrombosis are common in severe cases of COVID-19 and are known causes of elevated PAP [32, 33]. Pulmonary hypoxia with hypoxic vasoconstriction was another likely cause of elevated PAP among our study patients [34]. Increased right chamber afterload due to mechanical ventilation is of course a common cause of elevated PAP in ICU patients in general.
Cardiac dysfunction was not associated with an increased risk of death in our study. However, patients with cardiac dysfunction had a more complex course of disease with a greater need for renal replacement therapy and less ICU-free days. It is unclear if this is a causal relationship, or if cardiac dysfunction is a marker for more severe disease. In a sub-group analysis, RV dysfunction and elevated PAP were independently associated with an increased risk of death. This is consistent with findings from other studies of patients with ARDS and hospitalized patients with COVID-19 [13, 14]. Regrettably, the main cause of death was not registered in the present study, and patients were not systematically assessed for pulmonary embolism. It is, therefore, unclear if RV dysfunction and elevated PAP are only markers of more severe pulmonary disease, with a subsequent risk of pulmonary collapse and respiratory death, or if there are other direct causes as well. It seems reasonable to assume that patients with RV dysfunction, elevated PAP, or both will benefit from further investigation by computer tomography for diagnosis of pulmonary embolism, worsening of ARDS, COVID-19 typical infiltrates, or secondary bacterial infection. Furthermore, pulmonary vasodilators could be tried to see if there is improvement in RV function or decreased PAP [35]. In severe cases of COVID-19, RV dysfunction could be supportive in a decision to prepare for, or initiate, extracorporeal membrane oxygenation (ECMO).
Cardiac dysfunction was not easily detected by clinical characteristics. Our hypothesis was that cardiac dysfunction would be associated with a more severe clinical picture, such as higher levels of oxygen, respiratory support, or elevated lactate levels. The only variable associated with an increased risk of having cardiac dysfunction was a high dose of noradrenaline. It is likely because that critical illness from COVID-19 is such a severe respiratory disease, the contribution of cardiac dysfunction is not detectable by clinical variables in such a patient population. However, high doses of noradrenaline should be considered a marker for a more severe cardiovascular deterioration. In patients requiring noradrenaline > 0.20 µg/kg/min, cardiac dysfunction should be suspected and echocardiography ought to be performed.
The cardiac biomarkers troponin and NTproBNP only showed a moderate ability to detect cardiac dysfunction. However, a combination of troponin at less than 1.44 times its upper reference limit and NTproBNP < 857 ng/l had a negative predictive value of 85% of excluding cardiac dysfunction and might be used as a tool to rule out the need of echocardiography. This could be important in ICUs treating patients with COVID-19, where there is a need to conserve personal protective equipment and minimize the number of individuals interacting with contagious patients. On the other hand, levels above these limits had a predictive value of 81% for detection of cardiac dysfunction, suggesting that echocardiography should be performed.
Our study has some limitations. Inclusion rates were relatively low, as only 40% of the potential study population was included, mostly due to a lack of study resources. Moreover, a number of patients were retrospectively included. Nevertheless, a sensitivity analysis showed the study population was a representative sample of each site´s total population. The main strength of the study is the multi-centre design. Although the sample size is relatively low in absolute numbers, it is the largest study to date with echocardiographic evaluation, cardiac biomarkers, and clinical data carried out among COVID-19 patients in an ICU-setting.