Diagnosis and treatment of right ventricular dysfunction in patients with COVID-19 on veno-venous extra-corporeal membrane oxygenation

The outbreak of COVID-19 shocked many health care systems across the world, taking millions of lives [1‐5]. During H1N1 and MERS-CoV outbreaks, Mechanical circulatory support (MCS) had been utilized in severe cases refractory to optimal ventilator therapy and prone positioning with some success [6]. Although MCS has proved to be an effective salvage strategy in the immediate term in severe COVID-19 induced ARDS, the mortality rate has remained very high [6]. COVID-19 proved to have caused not only ARDS and respiratory failure but also right ventricular dilatation and dysfunction [7]. Right ventricular (RV) dilatation has been associated with significantly worse outcome in COVID-19 patients [7]. This phenomenon, likely reflects the increased afterload on the RV from secondary pulmonary hypertension as well as primary cardiomyopathic insult from the viral infection, often rendering VV ECMO strategy per se ineffective due to the resultant low cardiac output and end organ dysfunction. Utilization of right ventricular assist devices (RVAD) with oxygenators can mitigate both respiratory and right heart failure with some reported success [8]. Earlier case series have reported RV dilation to be present in as much as 41% of patients with COVID-19 induced ARDS and 27% of patients had impaired RV function [9] and identified C-reactive protein (CRP) and D-dimer as associated biomarkers of RV dysfunction [9‐11].

In this retrospective study we assessed our outcomes of MCS for COVID-19 patients in a regional high-volume center with a large geographic catchment area encompassing the pacific northwest of the United States. The aim of this study is to assess the effectiveness of VV ECMO in supporting patients with severe ARDS associated with COVID-19 as well as incidence of RV failure. We paid particular attention to the trends of the surrogate laboratory markers predicting RV dysfunction requiring inotropic and RVAD support. We trended end organ dysfunction, ICU length of stay, duration of mechanical circulatory support (if applicable), any complications related to right heart failure, and survival rate to hospital discharge. We also developed an algorithm (Fig. 1) to simplify early diagnosis of RV dysfunction and the need escalation of support (including placement of RVAD) before end organ dysfunction sets in.

The data was extracted from March 2020 to March 2021 from the regional University of Washington Extracorporeal Life Support database. All subjects were adults, 18 years or older, with COVID-19 infection, confirmed via reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 virus (i.e. COVID-19) with acute respiratory distress syndrome (ARDS). They all had refractory hypoxemia, requiring Veno-venous Extracorporeal Membrane Oxygenation (VV ECMO) hospitalized at the University of Washington Medical Center or Harborview Medical center in Seattle, Washington were included in this study. ARDS was diagnosed using the Berlin criteria [12] as follows: 1. Presence of acute hypoxemic respiratory failure, 2. Worsening respiratory symptoms within 7 days, 3. Cardiac failure not the etiology for respiratory failure and 4. Presence of bilateral opacities. The observation of bilateral pulmonary infiltrates in this study were done on computed tomography (CT) scan in keeping with the Berlin criteria for ARDS. Our patient cohort included patients across the WWAMIO region (Washington, Wyoming, Alaska, Montana, Idaho, and Oregon), covering a population of approximately 11.8 million people according to the U.S Census Bureau and approximately 1/5th of the USA landmass.

Institution Review Board (IRB) was obtained from the University of Washington research review board. Patients’ charts were accessed and reviewed. Information regarding basic demographic background (age, race, gender) as well as body mass index (BMI), comorbidities, and smoking history were gathered. The serial pre-VV ECMO cannulation arterial blood gases (ABG) and ventilator settings were obtained to assess whether the severity of ARDS and higher ventilator settings were correlated with RV dysfunction. Key organ functions were evaluated using surrogate peak biomarkers values for creatinine, aspartate aminotransferase (AST), troponin I, and brain natriuretic peptide (BNP). Transthoracic echocardiography (TTE) data for all patients that had a TTE performed during their hospital course were reviewed. RV dysfunction was defined as tricuspid annular plane systolic excursion (TAPSE) of < 17 mm or right ventricular fractional area change (RV FAC) of < 35% in accordance with the criteria developed by the American Society of Echocardiography [13]. Accordingly, patients were categorized into two groups: no RV dysfunction and RV dysfunction. The patients with no TTE studies were presumed to have no RV dysfunction and were placed in the no RV dysfunction group accordingly. The criteria for percutaneous right ventricular assist device (RVAD) support were RV dysfunction leading to hemodynamic instability and/or progressive end organ (liver and renal) dysfunction, and available ECMO capacity in the university hospital capable of managing patients with MCS. All RVADs were placed percutaneously in the hybrid suite and using the right internal jugular vein or left subclavian vein approach (Tandem Heart Protek Duo, dual lumen cannula). Additionally, the severity of lung injury was assessed using pre-VV ECMO ventilation settings, PaO2/FiO2 ratio, and ABGs. Hospital course and outcomes were evaluated by comparing rates of complications, survival to discharge, and duration of mechanical and circulatory support.

We identified 33 patients that met the aforementioned inclusion criteria, Baseline demographic characteristics, as well as risk factors and comorbidities, are summarized in Table 1. The mean age was 49 ± 9 years. 73% (n = 24) of patients were male. The majority of our patients were non-Caucasian (79%, n = 26). This was a significant finding as the WWAMIO region is overwhelmingly populated by white Caucasians, indicating ethnic minorities are more severely affected by COVID-19.

RV injury, dilation and dysfunction as a result of COVID-19 pneumonia is a well-recognized complication of this condition [7] and previous studies have objectively examined this phenomenon through echocardiography [11, 14] and magnetic resonance imaging (MRI)(15). It has been demonstrated that presence of RV dysfunction is a significant adverse prognostic indicator in severely ill patients with COVID-19 [10, 15‐17]. We identified that an overwhelming majority (78.8%) of the patients admitted needing VV ECMO for COVID-19 were of non-white ethnic background. This is significant in the WWAMIO region with predominantly white population. However, higher incidence and higher morbidity and mortality rates in the non-Caucasian ethnic minorities from COVID-19 is a well reported phenomenon that could possibly be explained by socioeconomic disparities and lack of access to health care [18, 19].

In this study of COVID-19 patients on VV ECMO, 42% of cohort demonstrated echocardiographic evidence of clinically significant RV dysfunction. This is remarkable as it confirms the previously shown high incidence of RV dysfunction within patients with ARDS secondary to COVID-19 reported by other studies [20‐22]. Additionally, we identified that pre-existing chronic lung disease increases the risk of RV dysfunction by nearly threefold. As such these patients should be more attentively monitored for evidence of RV dysfunction using TTE, particularly with TAPSE and RV FAC measurements. A previous study by Lan et al. [10], demonstrated elevation in serum markers of D-Dimer and C-reactive protein (CPR) as surrogates of RV dysfunction. We do acknowledge that, while it is not possible to conclusively say which entity (RV failure or Troponin I/BNP elevation) preceded which, it is important to emphasize that Troponin I and BNP are highlighted as potential screening tools to detect and preempt RV failure earlier in its course, and any rise in these lab values should prompt trending these values in time and performing further investigation looking for evidence of RV dysfunction before “full on” RV failure and end organ dysfunction has set in. In this study, we identified that serum Troponin I and BNP were strong indicators of RV dysfunction. Our data showed troponin I elevation was sixfold and BNP elevation was fourfold higher in the RV dysfunction cohort as compared to the non-RV dysfunction cohort. Indicating that up-trending levels of these two markers should prompt physicians to monitor patients for RV dysfunction using TTE. We also recommend that any patient who requires VV ECMO due to COVID-19 should get a baseline and a follow-up TTE to monitor RV function.

Notably also we identified significantly higher thromboembolic phenomenon in patients after they developed RV dysfunction. It is known that COVID infection is a thrombogenic state. However, we also pustulate that higher venous pressures leading to greater stagnation of blood, predisposing patients to thromboembolic risk.

Furthermore, we report survival to hospital discharge of 39% amongst our COVID-19 patients who required VV ECMO. Our study could not further confirm findings by previous studies that reported higher mortality rates in patients with RV dysfunction. However, our study did demonstrate a trend towards increased length of hospitalization, as well as duration on mechanical and circulatory support in the RV dysfunction cohort. It is unknown whether RVAD support of patients with RV failure due to COVID ARDS improves mortality, and furthermore unknown if RVAD rescue of patients on VV ECMO with a failing RV is a viable option. This question is ripe for further study as some preliminary data suggest impressively high rates of survival in patients supported using RVADs. Mustafa et al. [23], reported a study of 40 consecutive patients undergoing VV ECMO for COVID-19 related respiratory failure. They reported that 29 (73%) were weaned off from ECMO and were eventually discharged from the hospital without need for further oxygen therapy. However, this study did not report any significant RV failure or the need for RVAD in of their patients, which is a unique feature of our report.

Based on the findings presented in this study we devised a flowchart algorithm (see Fig. 1) for evaluation, monitoring and management of COVID-19 patients on VV ECMO with respect to RV dysfunction.

In conclusion, we identified that a significant proportion of patients with COVID-19 infection requiring VV ECMO develop RV dysfunction. There is significant predilection of this phenomenon for ethnic minorities. Troponin I and BNP were identified as early biomarkers of RV dysfunction. This study reinforces the standard of care of obtaining baseline and serial TTE in these critically ill COVID-19 patients on VV ECMO. A close and systematic assessment during the ECMO Support with biomarkers and echocardiography might predict impairment and evolution towards RV failure and properly change the therapeutic approach including percutaneous RVAD support.

In our study not all patients had echocardiography, in whom laboratory surrogates were utilized as markers of RV failure. This study is inherently limited by limited number of subjects as well as its retrospective nature.