The prognostic role of right ventricle dilatation and dysfunction (RVDD) has not been elucidated in patients with coronavirus disease (COVID)-related respiratory failure refractory to standard treatment needing extracorporeal membrane oxygenation (ECMO) support.

To assess whether pre veno-venous (VV) ECMO RVDD were related to in-intensive care unit (ICU) mortality.

We enrolled 61 patients with COVID-related acute respiratory distress syndrome refractory to conventional treatment submitted to VV ECMO and consecutively admitted to our ICU (an ECMO referral center) from 31^th March 2020 to 31^th August 2021. An echocardiographic exam was performed immediately before VV ECMO implantation.

Males were prevalent (73.8%) and patients with a body mass index > 30 kg/m² were the majority (46/61, 75%). The overall in-ICU mortality rate was 54.1% (33/61). RVDD was detectable in more than half of the population (34/61, 55.7%) and associated with higher simplified organ functional assessment (SOFA) values (P = 0.029) and a longer mechanical ventilation duration prior to ECMO support (P = 0.046). Renal replacement therapy was more frequently needed in RVDD patients (P = 0.002). A higher in-ICU mortality (P = 0.024) was observed in RVDD patients. No echo variables were independent predictors of in-ICU death.

In patients with COVID-related respiratory failure on ECMO support, RVDD (dilatation and dysfunction) is a common finding and identifies a subset of patients characterized by a more severe disease (as indicated by higher SOFA values and need of renal replacement therapy) and by a higher in-ICU mortality. RVDD (also when considered separately) did not result independently associated with in-ICU mortality in these patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease can evolve in some cases in severe respiratory failure, refractory to conventional therapies, which requires veno-venous extracorporeal membrane oxygenation (VV ECMO) support, possibly in experienced centers[1-3]. In coronavirus disease (COVID) respiratory disease, right ventricular (RV) dilatation is frequently encountered especially in severe disease[4,5], but, to date, the prognostic role of RV dilatation has not completed elucidated. In acute respiratory distress syndrome (ARDS) from different etiologies on ECMO support[3] RV dilatation and dysfunction (RVDD) were negatively associated with early outcome, while the prognostic role of RVDD has not been elucidated in patients with COVID-related respiratory failure refractory to standard treatment needing ECMO. We hypothesize that pre ECMO RVDD is related to in-intensive care unit (ICU) mortality, and we tested this hypothesis in 61 consecutive patients with COVID-related ARDS on ECMO support.

In our prospective observational study, we enrolled 61 patients with COVID-related ARDS refractory to conventional treatment submitted to VV ECMO and consecutively admitted to our ICU (an ECMO referral center) from 31^th March 2020 to 31^th August 2021. No exclusion criteria. The study protocol was approved by our Ethical Committee (“Comitato Etico Area Vasta Centro” n.17024, approved on March 31^th 2020) (“Florence COVID ICU Registry”). The written inform consent for each patient was waived for emerging infectious disease. The need for ECMO support was communicated to the patient’s relatives by phone before implantation.

On ICU admission we measured: Troponin (pg/mL), N-terminal-pro brain natriuretic peptide (NT-BNP, pg/mL), C-reactive protein (mg/dL) creatinine (mg/dL), lactose dehydrogenase (UI/L), D-dimer (ng/mL), and interleukin 6 (pg/mL). According to our echocardiography protocol[3,5], an echocardiographic exam was performed immediately before ECMO implantation. Systolic pulmonary artery pressure (sPAP) is obtained using the simplified Bernouilli’s equation. RVDD was defined in presence of RVEDA/LVEDA > 0.6 and tricuspid annular plane systolic excursion (TAPSE) < 15 mm (M-mode). Coupling of RV function to the pulmonary circulation was evaluated as the TAPSE to sPAP ratio. Each echo measure is performed three times, and the mean value was recorded[4,6].

All ultrasound cardiac procedures were performed using the necessary protective equipment for professionals. Dedicated machines (Ge HealthCare machine) were used in the COVID ICU and transducers are wrapped in single-use plastic covers. We considered VV ECMO in COVID when respiratory failure persisted despite optimum management including controlled ventilation with tidal volume 6 mL/kg, plateau pressure < 30 cm H₂O, use of neuromuscular blockers, high-positive end-expiratory pressure, and repeated prone positioning sessions[1-3,7,8]. All patients were encouraged to mobilize early[3]. Outcome was death in the ICU.

Our population comprised 61 consecutive patients with COVID-related respiratory failure on ECMO support (Table 1). Patients transferred from peripheral hospitals accounted for the 62% of our population. Males were prevalent (73.8%) and patients with a body mass index > 30 kg/m² were the majority (46/61, 75%). Renal replacement therapy was needed in almost half of the entire population (48%). Renal replacement therapy was started on ICU admission in five patients (17%) and after ECMO start in the remaining 24 patients (83%). The overall in-ICU mortality rate was 54.1% (33/61). At echocardiography left ventricular ejection fraction (LVEF) was normal in all but three patients who had LVEF < 45% because of previously known heart disease.

The main finding of the present investigation is that, in COVID-related respiratory failure on ECMO support, RVDD (defined as the coexistence of dilatation and dysfunction) is a common finding. The presence of RVDD identifies a subset of patients characterized by a more severe disease (as indicated by higher SOFA values and need of renal replacement therapy) and by a higher in-ICU mortality. However, at logistic regression analysis, RVDD (even when considered separately) did not result independently associated with in-ICU mortality in these patients.

Growing evidence suggests that, in COVID respiratory failure, varEchoious echocardiographic patterns may be observed across disease severity progression, ranging from isolated systolic pulmonary hypertension to RVDD. Studies are quite often heterogeneous, especially in respect to selected echo parameters and definition of RV dysfunction and dilatation. In a small series of mechanically ventilated COVID patients, acute pulmonary hypertension (observed in the 39%) was associated with higher 30-d mortality[9]. Likewise, in a retrospective investigation including 214 patients, RV dysfunction, pulmonary hypertension, and moderate to severe tricuspid regurgitation were associated with increased odds for 30-d mortality[10]. In 98 consecutive COVID-related respiratory failure, three different subgroups were identified at serial echocardiograms according to the presence/occurrence and timing of RVDD (defined as the association of RVDD), that is admission RVDD, new onset RVDD, no RV changes. Admission and newly developed RVDD subgroups identified severe COVID respiratory disease which in a high percentage of cases needed ECMO support[11]. In the present investigation, the study population comprises the most severe state of COVID-related respiratory failure, refractory to standard treatment and requiring ECMO support in whom RVDD (dilatation and dysfunction) is quite common being detectable in more than a half of the entire population. Few data are available on echocardiographic data in patients with COVID-related respiratory failure on ECMO support.

In the series by Bleakley et al[11] quite a large proportion of enrolled patients (38/90, 42%) were on ECMO support, but they were not analysed separately. Kopanczyk et al[12] performed echocardiography in 11 consecutive patients on ECMO and observed that RV dysfunction (as indicated by abnormal free wall longitudinal strain and fractional area change) was present in the majority (9/11 patients). RV dysfunction was defined as RV dilatation (visual assessment) and abnormal septal motion in the study by Ortiz et al[13] who documented that no echo variable was predictor of outcomes (survival to discharge and survival to decannulation) in 64 COVID patients on ECMO (echocardiography performed post cannulation). In a small series of COVID patients on ECMO, we observed, by means of serial echocardiographic exams, that RVDD (defined as the coexistence of dilatation and dysfunction) may be reversible, especially in survivors[13]. We confirm and extend previous findings in a larger series, focusing on the prognostic role (if any) of RVDD for in-ICU death. According to our data, patients with RVDD showed a more severe disease (as indicated by SOFA) and a higher incidence of renal impairment (as inferred by the higher use of renal replacement therapy). Higher values of systolic pulmonary arterial pressure and of NT-pro BNP, observed in RVDD patients, suggest increased RV pressure which might contribute to renal impairment. The lack of differences in creatinine serum values between patients with RVDD and those without can be due to renal replacement therapy itself which does affect creatinine levels. Despite the higher in-ICU mortality observed in patients with RVDD, RVDD (even when considered separately) are not independent predictor of early death in our population. This might be due to several factors. Firstly, the high incidence of RVDD in these patients, in agreement with previous investigations[3,12,13]. Secondly, at serial echocardiographic assessments, RVDD may be reversible in COVID-related respiratory failure on ECMO support, though a percentage of critically ill COVID patients has been reported to develop RVDD during ICU course[13].

Finally, factors other than RV echo variables can independently predict in-ICU death in COVID-related refractory respiratory failure on ECMO support, such as age and duration of mechanical ventilation. The high frequency of RVDD may be responsible for the lack of association between echocardiographic data and mortality in our patients. Our results are in keeping with those reported by investigations enrolling only critically ill COVID patients who, similarly, were not able to detect a relation between mortality and RV dilatation[13].

In our series, multivariate logistic regression analysis identified the following predictors of in-ICU analysis: Age, severity of disease (as inferred by SOFA and creatinine values) and COVID-disease duration (indicated by time from symptoms’ onset) and mechanical ventilation pre-ECMO. A longer time from symptoms’ onset to ICU suggests more severe forms of disease, characterized by more pronounced pulmonary derangements, often unresponsive to therapy. Age is a well-known strong predictor in COVID respiratory failure, in line with recent evidence[1] and, though we enrolled patients aged < 65 years according to guidelines, the ROC-determined cut-off was 57 years in our series. Regarding the duration of pre-ECMO mechanical ventilation to date there is no clear indication on the optimal duration of mechanical ventilation before ECMO implantation in COVID disease. Extracorporeal Life Support Organization guidelines report that a period of more than 10 d of mechanical ventilation should be considered a contraindication for ECMO support, while a period of 7 d is reported as a cut-off by other studies[1,2].

In patients with COVID-related respiratory failure on ECMO support RVDD (dilatation and dysfunction) is a common finding and identifies a subset of patients characterized by a more severe disease (as indicated by higher SOFA values and need of renal replacement therapy) by a higher in-ICU mortality. RVDD (also when considered separately) did not result independently associated with in-ICU mortality in these patients.