Single echocardiographic parameters and association with hospital mortality
Regarding the secondary outcomes focusing on the association between single echocardiographic parameters and hospital mortality, we found that non-survivors had higher lateral E/e’ ratio (p=0.03). A trend towards higher average E/e’ ratio was also found (p=0.08), whilst septal values were not significantly different (p=0.31). Deceleration Time, a parameter used in previous guidelines (ASE/EACVI 2009) for the assessment of LVDD31, was significantly different according to hospital survival (p=0.01). The only other echocardiographic parameter significantly associated with hospital survival was the TDI s’ wave. This result was consistent with all measurements performed as septal, lateral and average (p=0.02; p=0.02; and p=0.01, respectively).
PRICES Checklist for reporting echocardiography studies are provided as Supplementary Digital Contents (1, for the checklist of the common items; 2, for checklist of the echocardiography variables studied). All the essential items of the LV diastolic function domain were reported, together with several items of the LV systolic function and RV function ones.
DISCUSSION In this small single center study conducted in patients with COVID-19 admitted to ICU, full assessment of LV diastolic function according to the ASE/EACVI 2016 guidelines20 was feasible in roughly three quarter of the population. The challenge of performing this assessment in the remaining patients is not entirely surprising as the assessment requires a good apical four-chamber acoustic window with proper alignment, recording and calculation of several parameters. Several factors may contribute to the challenges of properly assessing LVDD in COVID-19 patients. First, considering the severe respiratory impairment of this population of patients and the use of high positive end-expiratory pressures (median 10 cmH2O in our study), it is not unusual to experience suboptimal acoustic windows. Second, performing advanced CCE under hazardous conditions wearing personal protective equipment and double gloves may be challenging, especially during a period of unprecedented clinical workload; in such cases, advanced assessment of LVDD may be perceived as cumbersome and time-consuming, and it is unlikely to become a priority in a busy and understaffed ICU. Further, severe COVID-19 patients are frequently treated with prone position, which may render more complex the assessment with CCE32,33.
With several limitations, this study is probably one of the few available experiences reporting full LVDD assessment according to the current ASE/EACVI 2016 guidelines20. Indeed, whilst several studies reported behavior of one or more echocardiography variables used for the assessment of LVDD, it seems no studies have reported full LVDD assessment according to latest guidelines20, as shown by a systematic review9. From an overview of the literature on COVID-19 patients, we also could not find any experiences comparing the full and the simplified assessment of LVDD.
Unfortunately, our study is severely underpowered for detecting influence of LVDD on the outcome of severe COVID-19 patients. This was behind our control as the ICU served as COVID-ICU for the Trust only for a brief period of time (~4 months, n=102 COVID-19 admissions); moreover, the workload did not always allow timely assessment with advanced CCE for the purpose of this study, as only one operator had advanced CCE skills and joined the ECHO-COVID study. Therefore, all together with the risk of statistical error, it is likely that an inevitable selection bias took place.
We found that almost half of COVID-19 patients were diagnosed with LVDD according to ASE/EACVI 2016 guidelines20 (n=12/26, 46%). LVDD was associated with a trend towards higher mortality in those with LVDD according to ASE/EACVI 2016 guidelines20 (hospital, p=0.11; ICU, p=0.13). Conversely, the assessment of LVDD according to simplified Lanspa criteria30 showed no statistical differences; of note, LVDD diagnosis with the latter criteria was made in over 80% of patients (n=21/26), demonstrating significant differences with the assessment according to ASE/EACVI 2016 guidelines20. The reason of this striking difference relies probably in the large amount of patients with depressed TDI e’ wave values in the overall population; indeed, depressed e’ velocity is the only criteria adopted by Lanspa et al.30 for the diagnosis of LVDD. Moreover, applying the simplified Lanspa criteria for LVDD grading30 (based on values of E/e’ ratio) over half of patients had grade III LVDD (n=11/21) followed by grade II (n=7) and grade I (n=3). Taken together, these results show huge differences in the assessment of LVDD and probably the use of the simplified criteria for diagnosis and grading of LVDD in patients with severe COVID-19 should be considered cautiously as likely to produce some degree of overestimation. For instance, half of the patients diagnosed with normal LV diastolic function according to the ASE/EACVI 201620, had grade II (n=3) or III (n=4) LVDD according to the simplified definition30.
Bearing in mind the limitations of the study, we think that our analysis is in line with previous experience reporting the possible importance of LVDD in the context of critical illness. Different phenotypes of cardiovascular dysfunction have been described in critically ill patients34, and LVDD has received attention for its association both with mortality in septic patients21,22and for weaning failure23. Conversely, LVSD has not shown the same association when evaluated by means of LVEF35 or s’ wave24 in critically ill patients. It was somewhat unexpected to find that TDI s’ wave was significantly lower in hospital (and ICU) non-survivors, as this parameter has not been found associated with prognosis in critically ill patients (i.e. septic patients24); moreover, the population we studied was mostly free from cardiovascular support (77%), and those on norepinephrine received a very low dose (0.04 mcg/kg/min). However, considering that a myocarditis-like pattern has been found in cardiac magnetic resonance imaging after COVID-19 also in cohorts of asymptomatic and mildly symptomatic patients12,36,37, it is possible that the lower TDI s’ values are related with an impaired longitudinal LV systolic function not detected by assessment of LVEF.
We also found that lateral E/e’ ratio was significantly higher in non-survivors at hospital discharge, followed by a trend in average E/e’ ratio (p=0.08). The mean difference between survivors and non-survivors was just over 3 points, opening the possibility that higher left atrial pressure contributes to poorer prognosis in patients with severe COVID-19. However, the overall values of E/e’ ratio were not very high (median value of average E/e’ was 10.8), and non-survivors presented median values of 11, well-below the cut-off suggested by the ASE/EACVI 2016 guidelines (E/e’ 14)20. From clinical perspectives, this finding is in line with lung edema and impaired gas exchange mainly triggered by interstitial pneumonia, with left atrial pressure playing a marginal role in these cases. In our opinion, it is reasonable that E/e’ ratio does not play a major role also in consideration of the gradual course of the COVID-19 disease. Indeed, in most of the cases evolving towards severe interstitial patterns, the progression happens over days or weeks. During this period, the patient has already experienced fever and dehydration. The admission to the Emergency Department or to other COVID-19 areas with prolonged oxygen support (high-flow or non-invasive ventilation) increases the likelihood of intravascular volume depletion due to sweating (fever) and poor water intake. In such cases, the presence of normal left atrial pressure may be related to a reduced circulating volume for the above-described reasons, and it does not necessarily reflect intrinsic myocardial relaxation. On the contrary, the TRvel (other parameter used for assessing LVDD) could increase during severe COVID-19 due to the occurrence of micro- or macro-vascular thrombosis/embolism in the pulmonary circulation or for the effects of mechanical ventilation, rather than as a reflection of an ongoing impaired LV relaxation (post-capillary). Therefore, there are several adjunctive differences and peculiarities that may render the evaluation of LVDD even more complex as compared to the usual ICU patient. Among these, COVID-19 usually has a more gradual evolution of the critical illness as compared to typical septic shock evolving more rapidly.