J.J. van der Heijden, C.L. Meuwese, S.A. Braithwaite Departments of Intensive Care and Cardiothoracic Anaesthesiology, University Medical Centre, Utrecht University, Utrecht, the Netherlands
J.J. van der Heijden – email@example.com
ECMO as rescue for COVID-19 related ARDS: the pros and cons
Using extracorporeal membrane oxygenation (ECMO) as rescue respiratory support for COVID-19 related ARDS may be seen as a controversial use of scarce and stretched resources in the context of a global pandemic. We present two cases of COVID-19 related ARDS both requiring ECMO support in an experienced ECMO tertiary centre. The cases illustrate the decision-making concerning the initiation of ECMO during lifethreatening COVID-19 related respiratory failure. Both patients encountered the typical complications during extensive ECMO support, but with a completely different outcome. To identify patients that really benefit from this potentially life-saving support modality and attain meaningful functional outcome in addition to survival, remains a matter of debate.
Despite the enormous number of patients with confirmed COVID-19, only few are supported with ECMO for obvious reasons such as lack of resources and expertise in combination with high demand of staffing and costs, plus the highly available alternative of mechanical ventilation. At the beginning of the pandemic there were several reports stressing these important factors[1,2] and the outcome of first published ECMO cases was very disappointing. Overall, expert opinion was to reserve ECMO support for younger patients without comorbidity and multi-organ failure who had been on mechanical ventilation for less than a week. However, the confrontation of healthcare workers with many relatively young patients with severe ARDS and the publication of more case series from China and Italy with a better outcome[5,6] resulted in an increasing number of ECMO patients. Interim Extracorporeal Life Support Organization guidelines that appeared in April 2020 also shifted to a slightly more liberal approach, for example by including patients who had been on mechanical ventilation for up to two weeks. In this context, the following patients presented to our hospital during these early months of 2020, also known as ‘the first wave’.
A 46-year-old male with no previous medical history was referred via a nearby hospital because of progressive respiratory failure despite mechanical ventilation with high ventilator settings, including a 100% fraction of inspired oxygen. His symptoms started two weeks earlier, including fatigue, fever and dyspnoea. Polymerase chain reaction confirmed the presence of SARS-CoV-2 RNA. He was treated with hydroxychloroquine and ceftriaxone; bacterial blood and sputum cultures remained negative.
At presentation to our hospital the patient was deeply sedated in the prone position with ongoing neuromuscular blockade and he had been on mechanical ventilation for seven days. Ventilator settings had been set at: pressure control level 14 cm H₂O above PEEP 22 cm H₂O, frequency 20/min, I:E ratio 1:1, and fiO₂ 100%. Despite the extreme ventilator settings and prone positioning, an arterial blood gas showed severe respiratory acidosis (pH 7.12, PaCO₂ 95 mmHg and bicarbonate 30.0 mmol/l) in combination with a low P/F ratio (63). Chest X-ray showed diffuse shadowing with air bronchograms and bilateral consolidations (figure 1a).
After a short and unsuccessful trial of inhaled nitric oxide, we decided to initiate peripheral veno-venous (V-V) ECMO the same day. In order to perform cannulation, the patient was turned to the supine position, at which oxygen saturation dropped to 80% but the patient remained haemodynamically relatively stable with a sinus tachycardia of 120 beats/min and invasive blood pressure of 120/70 mmHg with a minimal dose of vasopressors.
Ultrasound-guided cannulation followed (23 and 19 French cannulas inserted in the right femoral and right internal jugular vein, respectively). Sweep gas flow via the ECMO system was started at 2 l/min, which was slowly increased to 10 l/min to prevent a rapid correction of arterial PaCO₂. Blood flow was kept at 4 l/min. Ventilator settings were adjusted to allow as much ‘lung rest’ as possible: pressure control level 12 cm H₂O above PEEP 14 cm H₂O, frequency 8/min, I:E ratio 1:2, and fiO₂ 80%.
A bronchoscopy was performed on day 1 which showed oedematous airways without purulent secretions. Bacterial cultures obtained during bronchoalveolar lavage showed no pathogenic micro-organisms and a negative Aspergillus antigen index (0.16). Antibiotics were stopped on admission until blood cultures demonstrated Enterococcus faecium on day 6 for which the central lines were changed and vancomycin was started. Vancomycin was continued until after decannulation because of a second positive blood culture with Staphylococcus epidermidis despite adequate levels of vancomycin. Kidney function remained normal with an adequate clearance. During admission we regularly aimed for a negative fluid balance using intravenous furosemide.
Due to the lack of respiratory improvement, a CT scan of the chest was performed on day 13. It showed severe bilateral consolidations with ground glass opacities in combination with bilateral pleural effusion, possibly fitting empyema (figure 2). There were no signs of pulmonary embolism. After draining and culturing pleural effusion and repeating bronchoalveolar lavage, meropenem was started to anticipate the possibility of Pseudomonas species or other ceftriaxone-resistant micro-organisms.
Bacterial cultures, however, remained negative and meropenem was stopped after five days. The Aspergillus antigen index also turned out to be negative again (0.25). As hyperinflammation seemed to be the cause of the stagnating clinical course, high-dose methylprednisolone (1 mg/kg/day for the first 2 weeks) was started.
Our patient improved in the following days allowing us to lower the ECMO settings for the first time. Ventilator settings were gradually increased in the weaning phase of the ECMO support, unfortunately resulting in a pneumothorax on day 19. After drainage, however, it was possible to switch to pressure support and continue ECMO weaning. Decannulation took place on day 21 which was immediately followed by fever (max 39.6 ºC). Because repetitive blood cultures remained negative after stopping vancomycin, we interpreted this as the frequently observed systemic inflammatory response syndrome after ECMO decannulation.
Sedation was stopped on day 25 and the patient awoke the following day. Because of severe ICU-acquired weakness, a tracheostomy was performed on day 27 and after another week he was weaned off mechanical ventilation. A chest X-ray on day 30 showed clear improvement of the pulmonary abnormalities (figure 3). He was discharged to the medical ward on day 37 and transferred to a rehabilitation centre on day 56. Besides some remaining peripheral weakness of hands and feet, he recovered well. He lives at home, has good quality of life and resumed work completely.
A 60-year-old fit and active male with normal stature and a recent medical history including bronchial hyperreactivity, type 2 diabetes mellitus and radiotherapy for prostate carcinoma was admitted to a referring hospital three weeks before presentation at our centre.
He was diagnosed with COVID-19 and treated with hydroxychloroquine and high-flow oxygen. After four days he was transferred to the ICU because of progressive respiratory failure. He was intubated and mechanically ventilated with intermittent prone positioning because of a low P/F ratio. Ceftriaxone was started on admission to the ICU and changed after two days to piperacillin/tazobactam due to persistent fever and increasing inflammatory parameters. Cultures, however, remained negative. Because of further respiratory deterioration on day 7, a CT angiogram of the chest was performed, which showed severe bilateral consolidations in combination with subsegmental pulmonary embolism. A therapeutic dose of low-molecular-weight heparin was started in combination with intravenous furosemide. The following days showed gradual clinical improvement, but after two weeks, ventilator settings had to be increased significantly and bronchoalveolar lavage was performed to search for ventilator-associated pneumonia. Piperacillin/ tazobactam was restarted awaiting results and the patient was transferred to our centre for possible ECMO indication.
At presentation ventilator settings were as follows: pressure control level 24 cm H₂O above PEEP 6 cm H₂O, frequency 30/ min, I:E ratio 1:1,5 and fiO2 60%. Arterial blood gas showed pronounced hypercapnia (pH 7.21, PaCO₂ 124 mmHg and bicarbonate 48.9 mmol/l) in combination with a low P/F ratio (112). Compliance was extremely low (11 ml/cm H₂O). We performed a new CT scan the same day which still showed severe bilateral consolidations and subsegmental pulmonary embolism. But now subpleural reticulation and some traction bronchiectasis could also be seen, possibly in the setting of pulmonary fibrosis (figure 4), matching low compliance. After extensive discussion in our ECMO team, taking into account the patient’s previous good functional status in combination with the fact he had yet to receive antiinflammatory therapy, we decided to start V-V ECMO support. Ultrasound-guided cannulation (25 French left femoral vein and 21 French right internal jugular vein) was followed by a second bronchoalveolar lavage and high-dose methylprednisolone (1 mg/kg/day for the first two weeks). The ventilator settings were changed to pressure control level 14 cm H₂O above PEEP 10 cm H₂O, frequency 12/min, I:E ratio 1:5 and fiO₂ 40%. Sedation and neuromuscular blockade could be stopped soon after and the patient awoke, changing to pressure support with tidal volumes around 4 ml/kg and acceptable breathing frequency (20-25/ min) using 3 l/min blood flow and 6 l/min gas flow.
Bacterial cultures remained negative as did the Aspergillus antigen index (0.09). Polymerase chain reaction on bronchoalveolar lavage material, however, was positive for Cytomegalovirus. Because of an increasing plasma Cytomegalovirus load the following week ganciclovir was started. A tracheostomy was performed in the setting of severe ICU-acquired weakness and after almost two weeks of physiotherapy gas flow could be slowly weaned, followed by decannulation on day 15. However, four days after removing the ECMO, he showed a rapid respiratory and haemodynamic decline. CT angiography showed a new pneumomediastinum and increase of bilateral consolidations without progression of pulmonary embolism or signs of right ventricular failure (figure 5). Ongoing ventilator-induced lung injury or even self-inflicted lung injury were suspected, possibly in combination with a new ventilator-associated pneumonia. Because hypoxaemia was not present at that time, we decided to go for a second ECMO run, but this time configured for extracorporeal CO₂ removal (ECCO₂R).
A 22 French duallumen cannula was inserted in the right internal jugular vein. Blood flow was started at 1.8 l/min but could easily be lowered to 1.1 l/min. Gas flow had to be increased from 5 to a maximum of 10 l/min to accomplish low respiratory drive. Cultures again remained negative.
A few days later he spontaneously developed a cerebellar bleed with a minimal hydrocephalus impeding mobilisation on ECCO₂R. The heparin ratio was in the lower normal range (1.5), but with a stable thrombocytopenia (70 x 10 ⁹/l) for which the oxygenator was replaced. He was treated conservatively and after a week recovered quite well. Physiotherapy and mobilisation could be restarted and gas flow could even be lowered to a minimum of 3 l/min. But during further episodes of central line associated bloodstream infections (Enterococcus faecium and Staphylococcus epidermidis) he remained highly gas flow dependent and delirious. This once again seemed to stop him from recovering further, so we decided to continue vancomycin as long as ECCO₂R was ongoing.
On day 57 of our ICU admission a new CT scan was taken to re-evaluate the pulmonary status (figure 6). Unfortunately, there were now also signs of honeycombing and an increase in subpleural cysts, fitting a diagnosis of progressive pulmonary fibrosis. Bilateral consolidations were still extensive, and a new left-sided pleural effusion was seen, possibly empyema. Bronchoalveolar lavage showed Sphingomonas paucimobilis for which meropenem was started; pleural effusion, however, remained negative. As an incidental finding, a spontaneous haematoma was also seen in the left-sided musculus teres major and subscapularis.
The case was extensively discussed with our lung transplantation physicians and the team decided to see if a workup towards lung transplantation would be feasible. Prerequisites were complete neurological recovery including resolution of delirium and a significant improvement of muscle strength leading to a chronic situation of home ventilation without ECMO. Although the delirium faded away and physiotherapy could be intensified, our patient slowly developed acute kidney injury and further lung transplantation screening revealed severe pulmonary hypertension (estimated systolic pulmonary pressure >100 mmHg) with echocardiographic signs of significant right-sided heart failure. Changing to veno-arterial-venous support by that time was found disproportionate. These findings were discussed with the family and after more than 100 days of ICU admission he died as a result of multi-organ failure.
We present two patients supported by ECMO for COVID-19 related ARDS. Both encountered multiple complications during a prolonged ICU admission. Their different outcomes represents the extreme results of such a challenging and expensive support modality. As reflected by our two cases, the most common reason for using ECMO in COVID-19 patients is as respiratory support for COVID-19 related ARDS meeting traditional criteria and not responding to conventional therapy. Prone positioning, neuromuscular blockade, optimising mechanical ventilation, recruitment manoeuvres and a trial of inhaled nitric oxide should all have been performed before initiating ECMO. Because of the severity of disease, a quick recovery is not to be expected and eligible patients must be in such a pre-hospital condition that they are able to recover from an ICU admission of weeks or even months. Looking at the limited data available on survival after ECMO support in COVID-19 patients, mortality seems comparable with other causes of ARDS. [8-10]
The presence of older age and important comorbidities, however, will surely reduce the probability of functional recovery after a complex ICU admission. Taking into account this uncertainty relating to eventual survival and functional outcome, the question should be asked in advance if such a long ICU trial is in line with the patient’s wishes.
Common ICU complications will inevitably occur such as central line associated bloodstream infections, ventilatorassociated pneumonia, delirium and ICU-acquired weakness. Continuous antibiotic therapy is often needed for Gram-positive bacteria in the context of colonisation of the ECMO circuit. Repeated changing of the oxygenator for this reason is not only expensive but can also be insufficient because of the remaining cannulas. Diagnosing ventilator-associated pneumonia is often difficult requiring repeated bronchoalveolar lavage as in our patients, potentially exposing healthcare workers to SARSCoV-2. Mobilisation on ECMO is normally feasible, but ongoing delirium significantly impeded the physiotherapy required for ICU-acquired weakness in our second patient.
A more ECMO-specific complication is coagulopathy secondary to consumption of clotting factors, for example due to ECMO oxygenator thrombosis, which can result in serious spontaneous bleeding such as the cerebellar bleeding in our second patient. Underdosing of anticoagulant therapy or an ongoing inflammatory response, however, can cause clinically significant thrombosis, especially in the setting of COVID-19. Besides a small thrombus in the inferior caval vein in our first patient and pulmonary embolism in our second patient, we did not detect severe thrombosis; however, such a diagnosis can easily be missed. Daily monitoring of coagulation tests (e.g. APTT/PT) or even thromboelastography is therefore mandatory in combination with a normal blood count with optional levels of anticoagulation (anti-Xa) and clotting factors (such as fibrinogen or antithrombin) on a regular basis. Even with optimal anticoagulation therapy, oxygenator thrombosis cannot always be prevented and regular system changes quite often remain necessary, especially in the early stage of ICU admission and hyperinflammation.
Downregulation of the immune system with or without immune suppressive therapy can lead to opportunistic infections or viral reactivation, such as Cytomegalovirus in our second patient. Some specific antifungal or antiviral therapy carries a high risk for worsening acute kidney injury, although our patients did not suffer from such drug-induced renal complications. Ongoing respiratory failure requiring high pressures of mechanical ventilation, heightens the risk of lung fibrosis and prolonged permissive hypercapnia in this setting can lead to vascular changes causing pulmonary hypertension and eventually endstage right ventricular failure with secondary multi-organ failure. Overcoming all these possible problems is already challenging but the bigger picture is to prevent the patient becoming chronically ECMO-dependent as seen in our second patient. Although lung transplantation in the setting of end-stage pulmonary failure after COVID-19 has been described, the shortage of donors and a pre-existing waiting list for organ donation plus the numerous risk factors in an ECMO-dependent recipient makes this a very undesirable option.
The usage of ECMO in the setting of COVID-19 related ARDS can be a life-saving decision that leads to the desired good functional outcome in a patient who otherwise would have inevitably died. At the same time, it is a scarce and expensive resource in the context of a global pandemic and it coincides with a long and often complicated ICU admission. Identification of patients that benefit most from ECMO in this specific setting remains difficult as no patient is exactly the same and disease progression cannot always be stopped. A careful assessment before initiating ECMO and recurrent evaluation during ECMO support seems mandatory, taking every above mentioned aspect into account.
All authors declare no conflict of interest. No funding or financial support was received.
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