Changes in Therapy and Outcome of Patients Requiring Veno-Venous Extracorporeal Membrane Oxygenation for COVID-19

Abstract

Background Coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation (vv-ECMO) is related with poor outcome, especially in Germany. We aimed to analyze whether changes in vv-ECMO therapy during the pandemic were observed and lead to changes in the outcome of vv-ECMO patients.

Methods All patients undergoing vv-ECMO support for COVID-19 between 2020 and 2021 in a single center (n = 75) were retrospectively analyzed. Weaning from vv-ECMO and in-hospital mortality were defined as primary and peri-interventional adverse events as secondary endpoints of the study.

Results During the study period, four infective waves were observed in Germany. Patients were assigned correspondingly to four study groups: ECMO implantation between March 2020 and September 2020: first wave (n = 11); October 2020 to February 2021: second wave (n = 23); March 2021 to July 2021: third wave (n = 25); and August 2021 to December 2021: fourth wave (n = 20). Preferred cannulation technique changed within the second wave from femoro-femoral to femoro-jugular access (p < 0.01) and awake ECMO was implemented. Mean ECMO run time increased by more than 300% from 10.9 ± 9.6 (first wave) to 44.9 ± 47.0 days (fourth wave). Weaning of patients was achieved in less than 20% in the first wave but increased to approximately 40% since the second one. Furthermore, we observed a continuous numerically decrease of in-hospital mortality from 81.8 to 57.9% (p = 0.61).

Conclusion Preference for femoro-jugular cannulation and awake ECMO combined with preexisting expertise and patient selection are considered to be associated with increased duration of ECMO support and numerically improved ECMO weaning and in-hospital mortality.

Keywords

SARS-CoV-2 - COVID-19 - respiratory distress syndrome - extracorporeal - membrane oxygenation - respiratory failure

Introduction

Since late 2019, coronavirus disease 2019 (COVID-19), caused by a novel coronavirus strain known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly spread over the globe causing a pandemic.[1] In addition to adequate lung protective mechanical ventilation, veno-venous extracorporeal membrane oxygenation (vv-ECMO) has been established as an invasive ultima ratio therapy to bridge refractory severe respiratory failure since the early beginning of the pandemic.[2] [3] [4] Noninvasive and invasive mechanical ventilation is part of the baseline therapy for acute respiratory distress syndrome (ARDS), however, patients with COVID-19-related ARDS often require high pressure invasive ventilation causing an increased incidence of ventilator-induced lung injury such as barotrauma.[5] [6] Although global registry data suggest comparable outcome of vv-ECMO patients suffering from COVID-19 and non-COVID-19-related ARDS, recent German data has indicated severely impaired outcome for COVID-19 patients.[4] [7] [8] [9] [10] [11] In fact, global data report mortality of 37% for ECMO patients suffering from COVID-19-related ARDS.[8] [11] In contrast, mortality in Germany is reported nearly twice as high with 71 to 73%.[7] [9] Furthermore, increased mortality has been described between the different infective surges for both international (approximately between 40 and 60%) as well as German data (approximately between 60 and 75%) indicating impaired outcome with the persistence of the pandemic.[7] [12]

To investigate possible changes and developments in the therapy and outcome of patients with vv-EMCO support for therapy-refractory COVID-19-related ARDS, we retrospectively analyzed all patients treated at our center and compared pre-, peri-, and postinterventional parameters of the four different infective waves between 2020 and 2021.

Patients and Methods

Patients, Study Design, and Follow-Up Period

All patients (n = 91) who underwent ECMO implantation for therapy-refractory COVID-19-related ARDS between March 2020 and December 2021 in our department were analyzed. Those with any kind of primary venoarterial ECMO support were excluded (n = 16). The remaining n = 75 patients with isolated vv-ECMO were included in the study and categorized according to the date of the ECMO implantation. During the study period, four surges (infective waves) of COVID-19 patients on the intensive care unit (ICU) were observed in Germany. In line with this, patients were assigned to four study groups: ECMO implantation between March 2020 and September 2020: first wave (n = 11); October 2020 to February 2021: second wave (n = 23); March 2021 to July 2021: third wave (n = 25); and August 2021 to December 2021: fourth wave (n = 20). Follow-up was performed for 6 months after hospital discharge for every survivor. [Fig. 1] reflects the four infective waves of the study period in the context of the quantity of COVID-19 patients on German ICU.

Fig. 1 Schematic illustration of the quantity of coronavirus disease 2019 (COVID-19) patients on German intensive care units (ICUs) between March 2020 and December 2021. Throughout the study period four infective surges (first to fourth waves) were identified. Patients with veno-venous extracorporeal membrane oxygenation for therapy-refractory COVID-19-related acute respiratory distress syndrome of each wave were prospectively enrolled in an institutional database and retrospectively compared regarding their peri-interventional morbidity and mortality.

Study Objectives

Preinterventional baseline data and concomitant diseases as well as peri-interventional morbidity and mortality were assessed and retrospectively analyzed. Weaning from vv-ECMO and in-hospital mortality were defined as primary endpoints. In addition, peri-interventional adverse events including acute kidney failure, neurological complications, and bleeding complications were defined as secondary endpoints of the study.

ECMO Implantation and Adjuvant Pharmacotherapy

Inclusion and exclusion criteria for vv-ECMO implantation followed the guidelines of the Extracorporeal Life Support Organization (ELSO) and evolved during the ongoing pandemic in line with the updated guidelines.[3] [4] [13] [14] [15] In line with the ELSO interim guideline our institutional standard operating procedure covers a list of relative contraindications such as age > 65 years, body mass index > 40 kg/m², high-dose vasopressors or immune deficiency, as well as absolute contraindications such as severe multiorgan failure, severe neurological injury, contraindication for anticoagulation, and preexisting life-limiting medical conditions (e.g., end-stage malignancy).[3] [15] In general, vv-ECMO was implanted on ICU onsite or in a remote hospital. Cannulation was performed percutaneously with sonographic guidance. For venous drainage femoral vein was cannulated with a 25-Fr multistage cannula in every patient. For return of oxygenated blood, either contralateral femoral vein or internal jugular vein was cannulated (15–19 Fr cannula). Patients with vv-ECMO implantation in a remote hospital were transferred to our center directly after implantation and therapy was pursued onsite. Thoracic X-ray examinations were routinely performed every few days. In addition, thoracic as well as cerebral computed tomography scans were performed directly after ECMO implantation and whenever clinically indicated. Pharmacotherapy of ECMO patients followed international recommendations and varied therefore throughout the pandemic. In general, therapy included application of antiviral medications (e.g., remdesivir), antibodies (e.g., convalescent plasma, casirivimab/imdevimab), immunomodulatory medications (e.g., glucocorticoids, tocilizumab), and immunoglobulins (Igs) in case of low serum IgM levels.

Statistics

Statistical analyses were calculated with SPSS Statistics 28 (IBM Corporation, Armonk, New York, United States). All results are displayed as mean values with the standard deviation respectively percentage of the whole. Due to the small groups sizes Gaussian distribution was not assumed and variables therefore compared by either nonparametric two-tailed Kruskal–Wallis tests or Fisher–Freeman–Halton tests. In case of statistically significant results (p < 0.05), additional post hoc analyses were performed by a Bonferroni correction or two-tailed Fisher's exact tests. Detailed results of post hoc analyses are displayed in [Supplementary Table S1] (available in the online version).

Results

Baseline Parameters and Concomitant Diseases of COVID-19 Patients

Baseline parameters and concomitant diseases before implantation of vv-ECMO are displayed in [Table 1]. In addition, [Fig. 2A] shows the corresponding graphical trends of the most relevant parameters. Throughout the pandemic, a constant decline of patient age (p = 0.05) as well as incidence of relevant concomitant diseases such as chronic renal insufficiency (p < 0.01), chronic obstructive pulmonary disease (p = 0.01), and nicotine abuse (p = 0.01) was observed. In contrast, the percentage of obese patients increased since the first wave. Blood gas analyses indicated hypercapnic pulmonary failure during the whole study period and additional hypoxic pulmonary failure in waves two and three.

Table 1 Baseline parameters and preexisting concomitant diseases

Parameter	First wave	Second wave	Third wave	Fourth wave	p-Value
	(n = 11)	(n = 23)	(n = 25)	(n = 20)
Age, y	58.6 ± 17.6	55.7 ± 7.7	53.5 ± 9.1	49.2 ± 10.6	0.05
Female gender, n (%)	2 (18.2)	3 (13.0)	8 (32.0)	6 (30.0)	0.41
Body mass index, kg/m2	29.7 ± 4.5	27.3 ± 5.1	32.2 ± 5.6	30.3 ± 4.5	< 0.01
Concomitant diseases
Cardiovascular disease, n (%)	2 (18.2)	5 (21.7)	1 (4.0)	4 (20.0)	0.23
Arterial hypertension, n (%)	8 (72.7)	20 (87.0)	17 (68.0)	7 (35.0)	< 0.01
Diabetes mellitus, n (%)	6 (54.5)	7 (30.4)	4 (16.0)	6 (30.0)	0.14
Renal insufficiency, n (%)	5 (45.5)	5 (21.7)	1 (4.0)	0 (0.0)	< 0.01
COPD, n (%)	5 (45.5)	14 (60.9)	7 (28.0)	3 (15.0)	0.01
Smoking, n (%)	9 (81.8)	18 (78.3)	13 (52.0)	7 (35.0)	0.01
Obesity, n (%)	5 (36.4)	7 (30.4)	18 (72.0)	9 (45.0)	0.03
Blood gases before ECMO
paO2, mm Hg	73.8 ± 20.4	56.8 ± 17.4	56.2 ± 13.2	63.9 ± 8.2	0.02
paCO2, mm Hg	75.3 ± 27.1	72.4 ± 33.5	68.5 ± 33.4	95.3 ± 44.1	0.61
FiO2, %	80 ± 20	94 ± 12	99 ± 3	99 ± 4	0.08
pH, /1	7.23 ± 0.14	7.23 ± 0.17	7.32 ± 0.12	7.19 ± 0.18	0.36

Abbreviations: COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; F_iO₂, fraction on inspired oxygen; p_aO₂, arterial partial pressure of oxygen; p_aCO₂, arterial partial pressure of carbon dioxide.

Note: Table shows preinterventional baseline parameters and concomitant disease of patients undergoing veno-venous extracorporeal membrane oxygenation (ECMO) due to therapy-refractory coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome. Results of post hoc analyses for statistically significant differences are given in [Supplementary Table S1] (available in the online version).

Fig. 2 Graphical trends and percentage change from first to fourth waves of different parameters of patients undergoing veno-venous extracorporeal membrane oxygenation (ECMO) for therapy-refractory coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome. (A) Preinterventional baseline parameters and concomitant diseases. (B) ECMO support and adjuvant therapy. (C) Outcome parameters. COPD, chronic obstructive pulmonary disease. *Parameter was not observed during the first wave, therefore no percentage change was calculated.

ECMO Support and Adjuvant Pharmacotherapy

[Table 2] displays details about the ECMO support as well as the pharmacotherapy for COVID-19. Graphical trends of the most important parameters are illustrated in [Fig. 2B]. We did not observe differences regarding the duration of the pre-ECMO course of disease. In fact, patients were admitted to the ICU about 9 days after the onset of the first COVID-19-related symptoms and ECMO was implanted about another 8 days later. The mean duration of mechanical ventilation of about 4 days before ECMO implantation did not change over the study period.

Table 2 ECMO support and adjuvant therapy

Parameter	Frist wave	Second wave	Third wave	Fourth wave	p-Value
	(n = 11)	(n = 23)	(n = 25)	(n = 20)
Days since first symptoms and ECMO, d	14.8 ± 11.0	17.2 ± 6.5	15.6 ± 5.7	15.6 ± 7.7	0.63
Days since first symptoms and ICU, d	9.7 ± 10.6	8.8 ± 6.1	8.2 ± 8.9	8.6 ± 5.2	0.72
Days since ICU and ECMO, d	5.1 ± 4.9	8.7 ± 6.6	8.4 ± 5.3	7.0 ± 7.1	0.25
Days since intubation and ECMO, d	3.8 ± 4.0	4.7 ± 5.3	4.9 ± 4.8	2.7 ± 3.5	0.48
ECMO parameters
Indication					1.00
ARDS	11 (100.0)	23 (100.0)	25 (100.0)	20 (100.0)
Awake ECMO, n (%)	0 (0.0)	1 (4.5)	1 (4.0)	4 (20.0)	0.19
Vascular access
Femoro-jugular, n (%)	4 (36.4)	13 (56.5)	24 (96.0)	18 (90.0)	< 0.01
Configuration change, n (%)	2 (18.2)	2 (8.7)	0 (0.0)	0 (0.0)	0.05
Adjuvant therapy
Antibiotics, n (%)	11 (100.0)	22 (95.7)	22 (88.0)	20 (100.0)	0.40
Antiviral drugs, n (%)	10 (90.9)	14 (60.9)	18 (72.0)	20 (100.0)	< 0.01
Steroids, n (%)	5 (45.5)	20 (87.0)	25 (100.0)	20 (100.0)	< 0.01
Convalescent plasma, n (%)	2 (18.2)	5 (21.7)	2 (8.0)	0 (0.0)	0.10
Inotropes, n (%)	6 (54.5)	10 (43.5)	14 (56.0)	0 (0.0)	< 0.01
Vasopressors, n (%)	10 (90.9)	21 (91.3)	24 (96.0)	19 (95.0)	0.87
Prone therapy, n (%)	11 (100.0)	21 (91.3)	21 (84.0)	18/19 (94.7)	0.55
Prone therapy before ECMO, n (%)	5 (45.5)	14 (60.9)	12/22 (54.5)	7/17 (41.2)	0.63
Type of anticoagulation					< 0.01
Heparin, n (%)	11 (100.0)	23 (100.0)	22 (88.0)	12 (60.0)
Argatroban, n (%)	0 (0.0)	0 (0.0)	3 (12.0)	8 (40.0)

Abbreviations: ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit.

Note: Table 2 shows device parameters and adjuvant therapy of patients undergoing veno-venous extracorporeal membrane oxygenation (ECMO) due to therapy-refractory coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). Results of post hoc analyses for statistically significant differences are given in [Supplementary Table S1] (available in the online version).

We observed a distinct change regarding ECMO cannulation technique between the first two and the last two waves. While femoro-femoral cannulation was used in most cases during the first wave, femoro-jugular access was predominant since the third wave (p < 0.01). In addition, configuration change from veno-venous to any kind of venoarterial configuration (first wave: vav-ECMO, n = 2; second wave: vav-ECMO, n = 1 and vva-EMCO, n = 1) due to ventricular failure or refractory hypoxemia was abandoned in our center within the second wave (p = 0.05). In contrast to that, awake ECMO was implemented and more frequently used during the fourth wave (20% of cases).

Just as these parameters of ECMO support changed during the pandemic, pharmacotherapy advanced a lot. While antiviral drugs were used since the very beginning, steroids became part of the standard therapy within the second wave and were therefore used in every patient of the last two waves. In contrast to that, application of convalescent plasma preparations completely vanished by the development of targeted antibody therapies.

Outcome of ECMO Support

[Table 3] shows the relevant outcome parameters of ECMO support and additional graphic trends are given in [Fig. 2C]. At time of the analyses of the data, one patient of the fourth wave was still on vv-ECMO support (running since 118 days). Therefore, some data of the fourth wave only cover 19 patients as indicated in [Table 3]. Overall ECMO support duration as well as ECMO support duration until successful weaning increased during the pandemic from 11 days in the first wave to 45 days in the fourth wave (312% increase, p < 0.01), respectively, from 9 days in the first wave to 39 days in the fourth wave (354% increase, p = 0.08). Maximum duration of ECMO support was 163 days (fourth wave), maximum support duration until successful device weaning was 131 days (fourth wave). While incidence of acute kidney failure requiring hemodialysis dropped from 81.8% in the first wave to 0% in the fourth wave (p < 0.01), incidence of other device-related adverse events such as stroke or bleeding complications were more often observed within the third and fourth wave. Same trends were observed for pulmonary superinfections (first wave: 0.0%, fourth wave: 75.0%, p < 0.01). In-hospital mortality was mostly caused by therapy-refractory respiratory failure in the first two waves (77.7% respectively 68.8% compared with 12.5 and 27.3%) and then shifted toward multiorgan dysfunction syndrome (0.0% in first two waves compared with 43.8 and 45.5%) and neurological injuries (0.0% respectively 12.5% compared with 31.3 and 18.2%).

Table 3 Outcome

Parameter	First wave	Second wave	Third wave	Fourth wave	p-Value
	(n = 11)	(n = 23)	(n = 25)	(n = 20)
Overall ECMO support duration, d	10.9 ± 9.6	13.0 ± 10.5	29.4 ± 32.2	44.9 ± 47.0	< 0.01
Adverse events
Multiorgan dysfunction, n (%)	4 (36.4)	4 (17.4)	9 (36.0)	5/19 (26.3)	0.46
Sepsis, n (%)	8 (72.7)	9 (39.1)	15 (60.0)	9/19 (47.4)	0.26
Kidney failure with hemodialysis, n (%)	9 (81.8)	5 (21.7)	5 (20.0)	0/19 (0.0)	< 0.01
Major bleeding, n (%)	1 (9.1)	3 (13.0)	9 (36.0)	2/19 (10.5)	0.11
Ischemic stroke, n (%)	0 (0.0)	4 (17.4)	1 (4.0)	2/19 (10.5)	0.33
Hemorrhagic stroke, n (%)	0 (0.0)	1 (4.3)	7 (28.0)	3/19 (15.8)	0.06
Intracranial bleeding, n (%)	0 (0.0)	6 (26.1)	11 (44.0)	3/19 (15.8)	0.03
Bowl ischemia, n (%)	1 (9.1)	2 (8.7)	2 (8.0)	0/19 (0.0)	0.55
Pneumothorax, n (%)	5 (45.5)	7 (30.4)	5 (20.0)	10/20 (50.0)	0.16
Lung bleeding, n (%)	2 (18.2)	4 (17.4)	2 (8.0)	4/20 (20.0)	0.60
Pulmonary superinfection, n (%)	0 (0.0)	1 (4.3)	6 (24.0)	15/20 (75.0)	< 0.01
ECMO weaning, n (%)	2 (18.2)	9 (39.1)	11 (44.0)	8/19 (42.1)	0.52
Support duration till weaning, d	8.5 ± 2.1	13.4 ± 10.6	28.0 ± 18.6	38.6 ± 46.9	0.08
In-hospital death, n (%)	9 (81.8)	16 (69.6)	16 (64.0)	11/19 (57.9)	0.61
Cause of death					< 0.01
Respiratory failure, n (%)	7 (77.7)	11 (68.8)	2 (12.5)	3 (27.3)
Neurological injury, n (%)	0 (0.0)	2 (12.5)	5 (31.3)	2 (18.2)
Sepsis, n (%)	1 (11.1)	3 (18.8)	1 (6.3)	1 (9.1)
Multiorgan dysfunction, n (%)	0 (0.0)	0 (0.0)	7 (43.8)	5 (45.5)
Other, n (%)	1 (11.1)	0 (0.0)	1 (6.3)	0 (0.0)
Alive at 6 mo	2 (18.2)	7 (30.4)	7/23 (30.4)	3/13 (23.1)	0.87
Persistent dyspnea, n (%)	1 (50.0)	4 (57.1)	5 (57.1)	1/2 (50.0)	1.00
Persistent oxygen therapy, n (%)	0 (0.0)	2 (28.7)	2 (28.6)	1/2 (50.0)	1.00
Cognitive disorders, n (%)	0 (0.0)	3 (42.9)	3 (42.9)	1/2 (50.0)	0.82

Abbreviation: ECMO, extracorporeal membrane oxygenation.

Note: Table 3 shows outcome of patients undergoing veno-venous extracorporeal membrane oxygenation (ECMO) due to therapy-refractory coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome. One patient of the fourth wave was still on ECMO support (day 118). Therefore, parts of the outcome parameters of the fourth wave only cover 19 patients. Results of post hoc analyses for statistically significant differences are given in [Supplementary Table S1] (available in the online version).

Meanwhile weaning rate numerically increased since the first wave more than two times; however, this was not statistically significant (p = 0.52). Similar trends were observed for in-hospital death (29% decrease since the first wave, p = 0.61). Follow-up revealed no late term mortality with every patient surviving the initial hospital stay being still alive after 6 months.

Discussion

COVID-19-related ARDS requiring vv-ECMO support is still challenging and related with a quite dismal prognosis. Recent studies suggested even further impaired survival from one infective wave to the next[7] [12]: We hereby analyzed all our center's ECMO patients to investigate potential developments and determinants in the therapy outcome. Although several advancements have been found and weaning rate and survival numerically increased since the beginning of the pandemic and outrun German average, in-hospital mortality stayed unsatisfyingly high compared with global data.

Since the very beginning of the pandemic, tremendous effort has been taken to investigate pathomechanism and therapeutic targets of SARS-CoV-2 infections.[16] Starting from repurposing well-established drugs to the development of new therapeutics and vaccines, pharmacotherapy has evolved throughout the reported 2-year study period in our cohort.[16] [17] Meanwhile, emerging new virus variants lead to increased transmissions resulting in periodic infective surges.[16] Both developments have affected our data, as we reported alteration in adjuvant pharmacotherapy of the analyzed EMCO patients. Furthermore, ECMO therapy itself evolved as we focused more frequently on femoro-jugular cannulation and awake EMCO from wave to wave indicating a learning curve. Femoro-jugular instead of femoro-femoral cannulation for vv-ECMO has been reported as advantageous in patients requiring high ECMO blood flow which is often the case in COVID-19 patients.[18] [19] In fact, the femoro-jugular configuration has been reported to be more efficient in oxygenation and it is also advantageous with the prone position of the patients.[18] [19] [20] As COVID-19 patients often required long-term vv-ECMO support with deeply impaired oxygenation and decarboxylation, as well as multiple prone positions, the advantages of femoro-jugular access have gained importance and were preferred in our center during the ongoing pandemic. On the contrary, the concept of awake ECMO is discussed as controversial in the literature.[21] [22] Although several case reports describe promising results for awake ECMO in patients with COVID-19-related ARDS, recent multicenter data could not prove this presumption.[21] [22] [23] [24] [25] However, in-depth analysis of our data revealed that of all six patients with awake ECMO, only a single patient had never been at any time on mechanical ventilation which goes in line with the multicenter data.[21] Nevertheless, four patients were successfully weaned and one patient was still awake on ECMO support at the end of the study period indicating a favorable weaning rate in our cohort. Therefore, both changes, preference of femoro-jugular instead for femoro-femoral cannulation and awake ECMO, have evolved within the pandemic with our center's increasing experience in the treatment of COVID-19-related ARDS.

ECMO therapy is associated with a variety of severe adverse events such as bleeding and neurological complications limiting the long-term outcome of patients.[26] [27] Probably due to the increased ECMO support duration, we consequently observed increased incidence of bleeding and neurological complications in the recent waves.[26] [27] Meanwhile, reported causes of death shifted from pulmonary reasons toward more diverse events, again underlining a learning curve as therapy for severe lung failure was pursued and not limited to a strict time span. Hereby, we were able to report successful weaning and discharge of patients with 4 months of continuous ECMO support. Prolonged ECMO run time with a median duration of 14 to 20 days has been described for COVID-19 patients in the literature.[15] Interestingly, already before COVID-19 patients with ultra-long term ECMO support of up to 260 days have been described with no disadvantages in survival compared with patients with regular support duration less than 2 weeks supporting our concept of continuing support in the absence of limiting adverse events regardless of the actual run time.[28]

Fortunately, we were able to report a continuous numerical decrease of the in-hospital mortality since the first wave which is in fact contrary and therefore superior to both German as well as international multicentric data.[7] [12] However, mortality of approximately 58% in the fourth wave was still distressingly worse than global outcome data of approximately 40% reported in the literature.[8] [11] Comparison with German multicentric data, however, revealed again favorable outcome for our center compared with the nationwide average.[7] [9] Therefore, question arises why outcome of ECMO for COVID-19-related ARDS is impaired in Germany.[7] [9] [29] Multiple explanations have already been discussed in the literature with patient selection and center expertise being the most valuable ones.[7] [9] [12] [29] In this context, Barbaro et al reported significantly impaired outcome of COVID-19 patients with vv-ECMO for inexperienced centers.[12] In addition, several studies have underlined substantial benefits for experienced ECMO centers with a specialized interdisciplinary ECMO team.[30] [31] [32] However, another study by Bailey et al reported worse outcome of high-volume ECMO centers compared with low-volume institutions that may have been related to a selection bias with high-volume center probably accepting a wider range of patients for ECMO support.[33] As an experienced and well-trained center providing both veno-venous as well as venoarterial ECMO therapy and being part of several ECMO-related research groups, we follow the mentioned interdisciplinary specialized team approach and generally accept a wide spectrum of patients for ECMO support.[34] [35] [36] In contrast to that, patient selection seems fundamentally responsible for the general high morbidity observed at our center as well as nationwide in Germany.[7] [9] [37] Especially patient age and prevalence of preexisting concomitant diseases such as chronic kidney or pulmonary diseases within the first waves are most likely related to the increased in-hospital morbidity.[7] [9] [37] In addition, German health care system has never been really overburdened by COVID-19 patients and therefore was able to provide ECMO to a large number of patients with little triage.[37] However, affected by a general learning curve, patient selection criteria for ECMO have been revised during the continuance of the pandemic and therefore probably impacted the outcome.[29] [38] In fact, our center's policy of inclusion and exclusion criteria to evaluate eligibility of COVID-19 patients for vv-ECMO from no contraindications except anticipated nonrecovery following the general ELSO guideline for vv-ECMO support to a list of strict relative and absolute contraindications as recommended by the evolving specific COVID-19-related ELSO guidelines.[3] [4] [13] [14] [15]

Limitations

The single-center and retrospective design of the present study obviously limits its scientific value. Furthermore, the correspondingly small group sizes prohibited propensity score matching. As COVID-19 therapy, in particular pharmacotherapy, distinctly improved throughout the pandemic, adjuvant therapy could most likely acts as a confounder of the results. In addition, we changed our standard anticoagulation regime from heparin to argatroban within the third wave, which may also impact the results in an uncertain manner. While the changes in outcome after ECMO therapy are multifactorial and the potential effects of the developments in adjuvant pharmacotherapy may exceed the potential effects of the developments in EMCO cannulation and extracorporeal circulation, ECMO therapy in general is a multidisciplinary team approach, and therefore we were able to report changes in the outcome of critically ill COVID-19 patients requiring vv-ECMO. In particular, we were able to report new insights from a German high-volume center broadening the general knowledge about ECMO therapy for COVID-19-related ARDS.

Conclusion

vv-ECMO support is still associated with high mortality in COVID-19 patients. Although advances in pharmacotherapy have been achieved, therapy improvements for ECMO support had only a minor effect on the weaning rate and in-hospital mortality. However, with greater knowledge and experience in the treatment of patients with vv-ECMO suffering from COVID-19-related ARDS during the pandemic, several modifications were implemented. In particular, preference for femoro-jugular cannulation and awake ECMO combined with preexisting expertise in ECMO therapy and careful patient selection may be considered to be associated with the observed increased event-free ECMO support duration, enabling constant numerical improvements of the outcome contrary to the German and global trend.

Conflict of Interest

None declared.

Acknowledgment

The figures were created with Biorender.com.

Note

Presented at the 42nd Annual Meeting of the International Society for Heart and Lung Transplantation, 27-30 April 2022, Boston, MA, USA.

Ethical Approval Statement

The study followed the principles of the Declaration of Helsinki and was approved by the local university ethics committee.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Authors' Contribution

M.B.I.: Conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, writing – original draft, writing – review and editing.

V.H.: Data curation, methodology, investigation, validation, writing – review and editing.

D.K.M.: Data curation, resources, investigation, validation, writing – review and editing.

T.B.: Data curation, resources, investigation, validation, writing – review and editing.

T.F.: Data curation, investigation, validation, writing – review and editing.

H.A.: Data curation, resources, investigation, validation, writing – review and editing.

I.T.: Data curation, investigation, validation, writing – review and editing.

P.A.: Data curation, investigation, validation, writing – review and editing.

A.L.: Data curation, methodology, project administration, resources, supervision, validation, writing – review and editing.

H.D.: Conceptualization, data curation, investigation, methodology, project administration, resources, supervision, validation, writing – review and editing.

U.B.: Conceptualization, data curation, investigation, methodology, project administration, resources, supervision, validation, writing – review and editing.

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Publication History

Received: 11 February 2023

Accepted: 16 March 2023

Article published online:
05 May 2023