ABSTRACT
Objectives
We hypothesized that in Sars Cov2 (COVID)-related refractory respiratory failure requiring ECMO support echocardiographic findings (just before ECMO implantation) would be different from those observed in patients with refractory respiratory failure from different etiologies.
Design
single center observational study.
Setting
Intensive Care Unit.
Participants
61 consecutive patients with refractory COVID-related respiratory failure (COVID series) and 74 patients with refractory ARDS from other etiologies (no COVID series), all needing ECMO support.
Interventions
Echocardiography pre ECMO
Measurements and Main Results
RV dilatation and dysfunction (RVDD) was defined in presence of RV End-diastolic area (RVEDA)/left ventricle (LVEDA > 0.6 and tricuspid annular plane systolic excursion (TAPSE) < 15 mm. Patients in the COVID series showed a higher BMI (p<0.001) and a lower SOFA score (p=0.002). In-ICU mortality rates were comparable between the two subgroups. At echocardiography, performed in all patients before ECMO implantation, the incidence of RV dilatation was higher n patients in the COVID series (p<0.001), who also showed higher values of sPAP (p<0.001) and lower TAPSE/sPAP (p<0.001). At multivariable logistic regression analysis, the presence of COVID-related respiratory failure was not associated with early mortality. The presence of RV dilatation and uncoupling of RV function and pulmonary circulation were independently associated with COVID-respiratory failure.
Conclusions
The presence of RV dilatation and an altered coupling between right ventricle function and pulmonary vasculature (as indicated by TAPSE/sPAP) are strictly associated with COVID-related refractory respiratory failure needing ECMO support.
INTRODUCTION
Veno-venous extracorporeal membrane oxygenation (VV ECMO) is used as a rescue supportive treatment in refractory respiratory failure from Sars-CoV2 infection (COVID)-infection (1) and from other aetiologies of Acute Respiratory Distress Syndrome (ARDS) (2-4).
Echocardiography has been recognized as a clinical tool in addressing patients with refractory respiratory failure requiring ECMO (independently of the aetiologies), particularly focusing on the interaction between the right ventricle (RV) and pulmonary vasculature (5,6). This abnormal interaction has been associated with adverse outcomes in ARDS from different aetiologies and COVID-related respiratory failure (7-9).
Autopsy studies and histological research strongly suggest a far greater degree of pulmonary vascular angiogenesis and diffuse endothelial inflammation (10) in COVID respiratory failure than previously seen in similar viral ARDS such as influenza (11). Differences in clinical characteristics and mortality were reported between COVID-related respiratory failure requiring ECMO and ARDS from other etiologies (12,13).
We hypothesized that, in COVID-related refractory respiratory failure requiring ECMO support, echocardiographic findings (just before ECMO implantation) would be different from those observed in patients with refractory respiratory failure from other etiologies.
METHODS
In our case series, we enrolled all patients with COVID-related refractory respiratory failure needing ECMO support consecutively admitted to our ICU (which is an Extracorporeal Membrane Oxygenation (ECMO) referral center, Azienda Ospedaliero-Universitaria Careggi) from 1st April 2020 to 30th November 2021. The study protocol was approved by our Ethical Committee (“Comitato Etico Area Vasta Centro”, number 17024, approved on March 31th 2020). The written inform consent for each patient was waived for emerging infectious disease.
Data were compared with a historical series of patients with refractory ARDS needing ECMO consecutively admitted to our ICU from 1st January 2018 to 1st January 2020. All participants (or their kin) signed a written inform consent for storing their clinical data. The study was approved by our Institutional Review Board (14).
According to our protocol, as previously described (14,15) echocardiography (transesophageal -TEE/transthoracic echocardiography -TTE in all patients) was performed at the same time in all patients, that is immediately before ECMO implantation. Echocardiography (TEE and TTE) was used for ECMO implantation. RV dilatation and dysfunction (RVDD) was defined in presence of RV End-diastolic area (RVEDA)/left ventricle (LVEDA > 0.6 and tricuspid annular plane systolic excursion (TAPSE) < 15 mm. Systolic pulmonary artery pressure (sPAP) is obtained using the simplified Bernouilli's equation: 4 • (Vmax tricuspid regurgitation)2 + central venous pressure (CVP). Each measure is performed three times, and the mean value was recorded. The ratio TAPSE/ systolic pulmonary arterial pressure (sPAP) was calculated to assess right ventricle/pulmonary artery coupling, as index of RV function (9,16).
All ultrasound cardiac procedures were performed using the necessary protective equipment for professionals.
All echocardiography tests were carried out in in strict respect to current guidelines for care of COVID-19 patients. Ventilatory parameters and blood gas analysis were measured simultaneously to echocardiogram.
Primary outcome was to assess whether echocardiographic parameters (measured before ECMO implantation) were associated with in-ICU mortality in the overall population (COVID and no COVID patients). Secondary outcome was to evaluate whether echocardiographic parameters are associated with COVID respiratory failure.
Statistical analysis
Data have been stored in a dedicated data-base and analyzed with SPSS for Windows 20.0 (SPSS Inc., Chicago, IL). P value less than 0.05 was considered statistically significant. Categorical variables are reported as frequencies and percentages; continuous variables are reported as mean ± standard deviation (SD) or median (interquartile range, IQR), as needed. Between groups comparisons are performed by means of chi-square (categorical data) or, for continuous data, with Student's t test or Mann-Whitney U test, as appropriate. Normality has been assessed with Kolmogorov-Smirnov one sample test. Univariable logistic regression analysis was used to detect significant unadjusted predictors of ICU death to build multivariable logistic model(s).
RESULTS
We tested our hypothesis in 61 consecutive patients with refractory COVID-related respiratory failure and in 74 consecutive patients with refractory ARDS from other etiologies, all needing ECMO support.
Table 1 shows the comparison between patients with COVID-related refractory respiratory failure (COVID series) and those with no COVID-related refractory respiratory failure (no COVID series), all needing ECMO support. The COVID series included 61 consecutively patients, mainly males (73.8%). The no COVID series comprised 74 consecutive patients, males being prevalent. In this subgroup, bacterial pneumonia was the cause of respiratory failure in 42 patients (42/74, 57%), influenza in 27 patients (27/74, 36%), trauma in the remaining 5 patients (5/74, 8%). Age was comparable between the two subgroups. Patients in the COVID series showed a higher BMI (p<0.001) and a lower SOFA score (p=0.002). In-ICU mortality rates were comparable between the two subgroups. At blood gas analysis, when compared to the no COVID series, patients in the COVID series showed lower values of pH (p<0.001) and PaO2 (p<0.001) and higher values of PaCo2 (p<0.001). At echocardiography, performed in all patients before ECMO implantation, the incidence of RV dilatation was higher n patients in the COVID series (p<0.001), who also showed higher values of sPAP (p<0.001) and lower TAPSE/sPAP (p<0.001). Left ventricular ejection fraction was lower in the no COVID series.
Table 1Study population
| COVID series n=61 | No COVID series n=74 | p value | |
|---|---|---|---|
| Clinical characteristics | |||
| Age (years), mean±SD | 54.3±10.3 | 51.5±13.5 | 0.172 (t) |
| Gender M/F, n (%) | 45/16 (73.8/26.2) | 48/26 (64.9/35.1) | 0.266 (χ2) |
| BMI, mean±SD | 32.9±5.3 | 28.4±7.5 | <0.001 (t) |
| SOFA, mean±SD | 8.6±2.7 | 10.4±3.9 | 0.002 (t) |
| Mechanical ventilation length (days), median (IQR) | 8 (6-11) | 11 (7-13) | 0.175 (U) |
| ECMO duration (days), median (IQR) | 22 (13-42) | 12.5 (9-26) | <0.001 (U) |
| LOS (days), median (IQR) | 25 (18-52) | 21 (12-36) | 0.081 (U) |
| ICU death, n (%) | 33 (54.1) | 31 (41.9) | 0.157 (χ2) |
| Blood gas analysis | |||
| PaO2/FiO2, n (%) | |||
| ≥300 | 0 (0.0) | 1 (1.5) | |
| 200-299 | 0 (0.0) | 3 (4.5) | 0.259 (χ2) |
| 100-199 | 9 (20.5) | 11 (16.7) | |
| <100 | 52 (85.2) | 51 (77.3) | |
| PaO2 (mmHg), median (IQR) | 62 (50-75) | 79 (66-101) | <0.001 (U) |
| PaCO2 (mmHg), median (IQR) | 78 (72-90) | 46.5 (35-67) | <0.001 (U) |
| pH, median (IQR) | 7.25 (7.20-7.32) | 7.32 (7.30-7.41) | <0.001 (U) |
| Echocardiographic data | |||
| LVEF (%) | 65 (60-70) | 55 (50-55) | <0.001 (U) |
| RV dil, n (%) | |||
| ≥0.50 | 38 (62.3) | 69 (93.2) | <0.001 (χ2) |
| <0.50 | 23 (37.7) | 5 (6.8) | |
| TAPSE (mm) | 18 (10-21) | 18 (15-21) | 0.565 (U) |
| sPAP (mmHg) | 60.8±9.4 | 49.7±9.5 | <0.001 (t) |
| TAPSE/sPAP (mm/mmHg) | 0.28±0.13 | 0.37±0.13 | <0.001 (t) |
BMI: body mass index, ICU: intensive care unit, LOS: length of stay, SOFA: simplified organ functional assessment, ECMO: extracorporeal Membrane Oxygenation. LVEF: left ventricular ejection fraction; RV: right ventricle; dil: dilatation; TAPSE: tricuspid annual plane systolic excursion; sPAP: systolic pulmonary arterial pressure; IQR: interquartile range, t: Student t-test, U: Mann-Whitney U test, χ2: chi square test.
At multivariable logistic regression analysis (Table 2), SOFA score was an independent predictor of in-ICU mortality. The presence of COVID-related respiratory failure was not associated with early mortality.
Table 2Multivariable logistic regression analysis (outcome: ICU death)
| OR | 95% CI | p value | |
|---|---|---|---|
| Model 1 | |||
| COVID (reference NO) | 1.147 | 0.404-3.256 | 0.797 |
| Age (1 year step) | 1.032 | 0.997-1.068 | 0.071 |
| SOFA (1 unit step) | 1.161 | 1.017-1.325 | 0.027 |
| pH (0.01 units step) | 0.973 | 0.931-1.016 | 0.216 |
| sPAP (1 mmHg step) | 1.031 | 0.986-1.078 | 0.175 |
| Nagelkerke R Square 0.194; Hosmer and Lemeshow test chi-square 4.99. p=0.759 | |||
| OR | 95% CI | p value | |
| Model 2 | |||
| COVID (reference NO) | 1.431 | 0.543-3.770 | 0.469 |
| Age (1 year step) | 1.028 | 0.994-1.063 | 0.106 |
| SOFA (1 unit step) | 1.175 | 1.031-1.340 | 0.015 |
| pH (0.01 units step) | 0.974 | 0.932-1.018 | 0.236 |
| TAPSE/sPAP (0.01 step) | 0.987 | 0.955-1.019 | 0.419 |
| Nagelkerke R Square 0.182; Hosmer and Lemeshow test chi-square 8.95. p=0.347 | |||
COVID: Sars-CoV2 infection, SOFA: simplified organ functional assessment, TAPSE: tricuspid annual plane systolic excursion; sPAP: systolic pulmonary arterial pressure; OR: odd ratio; CI: confidence interval.
As depicted in Table 3, the following parameters were independently associated with COVID-respiratory failure: BMI (p=0.018), pCO2 (p=0.005), TAPSE/sPAP (p=0.014) and the presence of RV dilatation (p=0.033).
Table 3Multivariable logistic regression analysis (outcome: COVID)
| OR | 95% CI | p value | |
|---|---|---|---|
| BMI /1 kg•m−2 step) | 1.173 | 1.028-1.339 | 0.018 |
| ECMO (1 day step) | 1.104 | 0.990-1.232 | 0.076 |
| PCO2 (1 mmHg step) | 1.089 | 1.026-1.156 | 0.005 |
| RV dil_(1 unit step) | 0.035 | 0.002-0.506 | 0.014 |
| TAPSE/sPAP (0.01 step) | 0.922 | 0.857-0.993 | 0.033 |
| Nagelkerke R Square 0.870; Hosmer and Lemeshow test chi-square 3.64. p=0.888 | |||
COVID: Sars-CoV2 infection, TAPSE: tricuspid annual plane systolic excursion; sPAP: systolic pulmonary arterial pressure; RV: right ventricle; dil: dilatation; ECMO: extracorporeal membrane oxygenation.
DISCUSSION
The main findings of the present investigation are as follows: a) when compared to no Covid series, hypoxia and hypercapnia are more common in the COVID series who are more frequently obese and needed ECMO support for a longer period; b) ICU mortality rates were comparable between the two subgroups. In our retrospective and hypothesis generating study, the presence of RV dilatation and an altered coupling between right ventricle function and pulmonary vasculature (as indicated by TAPSE/sPAP) seems to be associated with COVID-related refractory respiratory failure needing ECMO support.
The novelty of the present investigation is that we compared pre ECMO echocardiographic findings observed in COVID-related refractory failure to those documented in refractory respiratory failure from other etiologies. We recognized a peculiar echocardiographic pattern in the COVID series compared to the no COVID series, characterized by uncoupling of the right ventricular function to pulmonary circulation and RV dilatation. Caravita et al (17) reported in 21 COVID- mechanically ventilated patients that the hemodynamic profile of COVID-19 patients needing mechanical ventilation is characterized by low pulmonary vascular resistance associated with high cardiac output and LV filling pressured, as assessed by right heart catheterization. In our series we observed higher LVEF and higher values of e/e1 (suggesting high LV filling pressures) in agreement with data reported by Caravita et al (17). On the other hand, differently from Caravita et al (17) we documented high values of sPAP, suggesting increased pulmonary vascular resistance. This finding may be related to the differences in disease severity between our population (COVID respiratory failure refractory to standard treatment) and that by Caravita et al (17) (need of mechanical ventilation). In the series by Caravita et al (17) no patient needed ECMO support. In 352 ARDS patients, pulmonary vascular resistance (measured at right heart catheterization) was significantly higher in no survivors than in survivors (18). In this study (18), baseline pulmonary vascular resistance and pulmonary arterial compliance both predicted survivals.
Beyond diffuse alveolar damage with micro- and macro-thrombosis that characterize classic ARDS (18), COVID -related respiratory failure shows a far greater degree of pulmonary vascular angiogenesis and diffuse endothelial inflammation. The findings of RV dilatation and uncoupling between RV function and pulmonary circulation observed in our COVID series might be related to the above-described alterations in pulmonary vasculature characterizing COVID-related respiratory infection. The resultant RV function-pulmonary circulation uncoupling (as indicated by TAPSE/sPAP in our study) leads to the inability of the RV to meet the flow demands without excessive use of the Frank-Starling mechanism, inducing systemic venous congestion (19).
In our investigation, survival to hospital discharge did not differ in patients requiring ECMO support from COVID-related respiratory failure than those with ARDS from different etiologies. This is in keeping with recent analysis of outcomes of V-V ECMO initiated for ARDS secondary to COVID compared to V-V ECMO initiated for a mix of non-COVID etiologies of ARDS (4, 12). Differently from the studies by Yaqoob et al (4) and Raasvelt et al (12), in our study patients with COVID-related respiratory failure showed a higher BMI than those with ARDS from different etiologies. The high incidence of obesity in COVID population is recognized (21,22) and it has not been associated with worse outcome in a retrospective investigation including a large series (292 patients) with severe COVID-related respiratory failure (119 patients, 40.8%, treated with ECMO) (22).
In our series, iNO was not administered during ECMO support since our group documented that iNO administrated as rescue therapy was not able to ameliorate oxygenation nor pulmonary hypertension, (serial echocardiograms) in COVID-related severe ARDS (23). In 12 consecutive COVID-related ARDS inhaled NO administration did not influence systolic pulmonary arterial pressures nor RV dimension and function, as assessed by means of serial echocardiographic exams (baseline, 12 and 24 h since iNO start).
Limitation of the study. The main potential limitation may be represented by the fact that it is a single center investigation. However, the number of enrolled patients is quite consistent for a single center and all patients were treated by the same ICU team. In a recent multicenter trial (1), 190 COVID patients treated with ECMO were analyzed, enrolled in 35 hospitals during a five-month period (5.4 patients/hospital in the study period). Another possible limitation may be the fact that in our echocardiographic examinations we did not include Tricuspid Regurgitation (TR) grading. At our institution, we selected a limited number of echo parameters since, in most cases, the examination has to be performed in a short time, due to the critical conditions of our patients.
Conclusion
We assessed echocardiographic findings in patients with severe COVID respiratory needing ECMO support and compared them with patients with refractory respiratory failure from different etiologies requiring ECMO. All echocardiographic exams were performed immediately ECMO implantation. We documented that the presence of RV dilatation and an altered coupling between right ventricle function and pulmonary vasculature (as indicated by TAPSE/sPAP) are strictly associated with COVID-related refractory respiratory failure needing ECMO support.
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Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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