key: cord-265647-uvajk3ea
authors: Ahmadi, Zargham Hossein; Jahangirifard, Alireza; Farzanegan, Behrooz; Tabarsi, Payam; Abtahian, Zahra; Abedini, Atefeh; Sharifi, Mehrzad; Jadbabaei, Amir Naser; Mafhumi, Yadollah; Moslem, Ali; Sistani, Marjan; Yousefian, Sahar; Saffaei, Ali; Dastan, Farzaneh
title: Extracorporeal membrane oxygenation and COVID‐19: The causes of failure
date: 2020-07-17
journal: J Card Surg
DOI: 10.1111/jocs.14867
sha: 
doc_id: 265647
cord_uid: uvajk3ea

INTRODUCTION: Venovenous extracorporeal membrane oxygenation (VV‐ECMO) is a therapeutic strategy for the coronavirus disease 2019 (COVID‐19) induced acute respiratory distress syndrome (ARDS). There are inconclusive data in this regard and causes of VV‐ECMO failure are not yet understood well. CASE SERIES: Here, seven patients with COVID‐19‐induced ARDS who underwent VV‐ECMO introduced and causes of VV‐ECMO failure discussed. Medical records of seven COVID‐19 patients treated with VV‐ECMO were retrospectively evaluated to determine the clinical outcomes of VV‐ECMO. Oxygenator failure occurred in four patients whom needed to oxygenator replacement. Successful VV‐ECMO decannulation was done in three patients, however finally one patient survived. CONCLUSIONS: Hypercoagulability state and oxygenator failure were the most main etiologies for VV‐ECMO failure in our study. All patients with COVID‐19 undergoing VV‐ECMO should be monitored for such problems and highly specialized healthcare team should monitor the patients during VV‐ECMO.

and Middle East respiratory syndrome coronavirus-related ARDS. 4 Since the efficacy and safety of VV-ECMO in patients with COVID-19-induced ARDS are still unclear, here we report seven patients with COVID-19induced ARDS who underwent VV-ECMO.

This is a single-center study, based on a retrospective cohort analysis of cases treated at the Dr. Masih Daneshvari Hospital, Tehran, Iran, which is the main referral center for patients with COVID-19 in Iran. The VV-ECMO procedure was the same for all patients. In all patients with refractory hypoxemia not responding to noninvasive ventilation, endotracheal intubation was performed, using low tidal volume, with a maximum plateau airway pressure of 30 cm H 2 O. When necessary, the respiratory rate was increased to a maximum of 30 breath/min, which was the mainstay of lung protective ventilation. Patients with a PaO 2 / FiO 2 ratio inferior to 80 for 6 hours, or a PaO 2 /FiO 2 ratio inferior to 50 for 3 hours, were candidate for VV-ECMO, regardless of having high positive end-expiratory pressure and neuromuscular blockage. Transthoracic echocardiography was performed, and if left ventricular ejection fraction was less than 50%, VA-ECMO would be applied.

The console of the VV-ECMO was centrifugal pump system (Liva Nova Deutschland GmbH, München, Germany). The oxygenator was EOS hollow fiber oxygenator intended for long duration procedures (Liva Nova, Mirandola, Modena, Italy). The drainage femoral cannula was RAP FV two stage 23 out of 25 (Liva Nova), which was inserted by close Seldinger's maneuver in the left or right femoral vein. The return cannula was a 23-F Easy Flow DUO arterial femoral cannula (Liva Nova), inserted by close Seldinger's maneuver in the right internal jugular vein. The position of the cannula was verified by chest x-ray, as well as by evaluating the efficacy of the system, by increasing the arterial oxygen saturation and partial pressure of arterial oxygen. The bolus dose of heparin (50 units/kg) was injected before cannulation. ECMO was initiated if activated clotting time (ACT) was in the range of 150 to 180 seconds. The heparin infusion would be continued at dose of 10 to 20 units/kg to maintain aPTT between 50 to 70 seconds. The rate of infusion was adjusted according to aPTT result, which was checked every 6 hours.

During the index period, patients with severe ARDS were referred to our institution. We evaluated seven COVID-19 cases that underwent VV-ECMO because of severe ARDS. The median age of patients at the time of hospitalization was 45 years (range, 26-71 years). One patient was female and the rest were male. All patients complained of high-grade fever, cough, and dyspnea at admission time. The median time from symptom onset to hospitalization was 7 days (range, 5-12 days). All patients had at least one underlying disease.

A combination of hydroxychloroquine and lopinavir/ritonavir were administered to all patients according to Iranian national guideline. 5 During the implantation of VV-ECMO, all patients had severe hypoxemia (peripheral oxygen saturation between 30%-60%). Only 1 patient was discharged with a stable condition.

Clotting formation in the oxygenator was seen in four patients, in first 5-day of VV-ECMO. Patients' details are summarized in Table 1 and the chest X-ray findings of patients at first day of VV-ECMO starting is shown in Figure 1 .

A 26-year-old male nurse with severe COVID-19 pneumonia was referred to the hospital. He complained of fever, cough, and dyspnea from 12 days before admission. For 3 days, he was intubated for invasive mechanical ventilation due to severe ARDS. His medical history showed a diagnosis of influenza H1N1 3 months before. He developed a worsening hypoxemia refractory to conventional ventilation. Chest x-ray showed a severe bilateral infiltration in both upper and lower lobes; therefore, he was treated with VV-ECMO.

The patient died after 3 days because of sudden hypoxia due to oxygenator failure of the VV-ECMO, causing clotting and subsequent cardiac arrest.

A 71-year-old man diagnosed with severe COVID-19 pneumonia was referred to the hospital. He complained of fever, cough, dyspnea, myalgia, and diarrhea from 7 days before. At admission, patient had severe hypoxemia and he was intubated for invasive mechanical ventilation due to ARDS. Chest x-ray showed a severe bilateral infiltration in both upper and lower lobes. After 2 days of invasive mechanical ventilation, hypoxemia persisted. The patient became oliguric (urine output less than 20 mL/h) and developed hemodynamic instability. Serum creatinine increased to 2.8 mg/dL.

He was treated with VV-ECMO and continuous renal replacement therapy. Then, oxygen saturation increased to 90%, whereas creatinine decreased to 2.6 mg/dL. However, after 7 days, the serum creatinine increased again from 2.6 mg/dL to 3.7 mg/dL, serum lactate dehydrogenase (LDH) increased to 3171 U/L, hemoglobin decreased to 7.6 mg/dL, and platelet decreased to 8700/L. The patient died due to multisystem organ failure.

A 56-year-old woman with severe COVID-19 pneumonia was referred to the hospital. She complained of fever, cough, dyspnea, myalgia, and diarrhea from 3 days before admission. Dyspnea persisted for the next 2 days and chest x-ray revealed progressive infiltration. Because of severe persistent hypoxemia, the patient was intubated for invasive mechanical ventilation; however, due to progressive hypoxemia, the VV-ECMO was applied 2 days later, and oxygen saturation increased to 96%. In the 5th day of VV-ECMO, she showed gradual hypoxia and elevated d-dimer, and the oxygenator was changed in the 6th day. Hypoxia was reversed and the patient's condition improved. After 8 days, she was weaned of VV-ECMO successfully. However, 24 hours after the removal of VV-ECMO, she 

A 45-year-old physician diagnosed with severe COVID-19 pneumonia was referred to the hospital. He complained of fever, cough, dyspnea, and myalgia from 6 days before admission. He was

The chest X-ray imaging of patients at first day of venovenous extracorporeal membrane oxygenation starting intubated due to severe ARDS. Chest x-ray showed a severe bilateral infiltration in both upper and lower lobes. The hypoxemia and lung infiltration progressed during hospitalization; therefore, the patient was treated with VV-ECM. Oxygen saturation increased to 95%. On the 4th day of VV-ECMO, the oxygenator was changed due to decreased oxygenation and hypercarbia. After 7 days, the patient's clinical condition improved and no metabolic disturbances occurred.

He was decannulated from extracorporeal support, although he developed convulsions after decannulation of VV-ECMO. Convulsions were not controlled by pharmacological interventions and extensive cerebrovascular accident happened and finally the patient died despite all efforts.

A 45-year-old man, diagnosed with severe COVID-19 pneumonia was referred to the hospital. He complained of fever, cough, dyspnea, and myalgia from 3 days before admission. After 2 days of hospitalization, hypoxemia occurred, and oxygen saturation decreased to 60%. Chest

x-ray showed a severe bilateral infiltration in both upper and lower lobes. Hence, the patient was intubated for invasive mechanical ventilation due to severe hypoxemia. However, hypoxemia persisted and he was treated with VV-ECMO. Following VV-ECMO, oxygen saturation increased to 95%. On the 5th day of VV-ECMO, oxygen saturation decreased and partial pressure of carbon dioxide increased.

The oxygenator was changed immediately and the aPTT was maintained in therapeutic range. The patient tolerated 9 days of VV-ECMO, and no significant complications occurred. The tracheotomy was performed and patient was transferred to ward under acceptable medical conditions. The management of this patient was improved in comparison with previous cases due to achievement of more experiences.

Coagulopathies and oxygenator failure did not occur and finally the patient was discharged after 5 days.

In some patients with ARDS, positive pressure ventilation may worsen the clinical condition and even multisystem organ failure may occur. VV-ECMO will benefit a selected patient population, such as those with severe ARDS. VV-ECMO is a highly specialized and very expensive form of advance life support and there are some guidelines, such as EMPROVE protocol, with proven outcomes in this regard. 6 The treatment of severe ARDS due to COVID-19 with VV-ECMO remains a challenge and controversial. 3, 7 Since some studies showed a higher mortality rate, compared with patients receiving only conventional respiratory care (100% vs 65%, respectively). 1, 8 The most important finding in these cases was the hypercoagulability state, with high rate of oxygenator failure, and the necessity to change it, which occurred at least twice than in other studies. 9 On the other hand, all patients were treated with continuous intravenous heparin to maintaining the aPTT between 70 and 90 seconds. Also, according to the results, our protocol changed and we suggest that for anticoagulation management of patients with COVID-19 under ECMO, aPTT should not be used. Instead of aPTT, ACT should be monitored and kept between 220 and 250 seconds.

We examined this protocol in two patients with satisfactory results.

Oxygenator dysfunction leading to oxygenator replacement was seen in 10% to 30% of VV-ECMO patients. Nevertheless, such rate was unusual, particularly among those without hepatic failure. 10 The fourth patient developed hepatic failure, probably due to a hypercoagulability state. The persistent hypoxemia in most patients might lead to rapid clinical deterioration, multi system organ failure and death. Another main issue was the late diagnosis of oxygenator failure, due to excess work load of nurses. On the basis of our study, and considering the evidence from Chinese patients, we think that the hypercoagulability state might be a phenomenon among severe cases of COVID-19 that requires to be carefully monitored.

Previous studies showed that the mortality rate related to VV-ECMO could be reduced if VV-ECMO is introduced within the first 7 days of mechanical ventilation. 13 In our cases, the high rate of mortality may be explained by the delayed implantation of VV-ECMO in patients under critical conditions. Future investigations should consider that since VV-ECMO is unlikely to improve patients' overall outcomes, if potentially fatal complications cannot be prevented.

Hypercoagulability state and oxygenator failure were the most important etiologies for VV-ECMO failure in COVID-19 patients with severe ARDS in our study. All patients with COVID-19 undergoing VV-ECMO should be monitored for such a phenomenon and managed meticulously to improve their survival. Moreover, the implementation of highly specialized healthcare team, state-of-the-art medical devices, and diagnostic laboratories are deemed indicated for enhancing care delivery.

Payam Tabarsi

Yadollah Mafhumi

Sahar Yousefian

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Continues renal replacement therapy (CRRT) with disposable hemoperfusion cartridge: a promising option for severe COVID-19

Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases

Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome

A fourteen-day experience with coronavirus disease

COVID-19) induced acute respiratory distress syndrome (ARDS): an Iranian treatment protocol

The impact of an advanced ECMO program on traumatically injured patients

ECMO for ARDS due to COVID-19

Association between hypoxemia and mortality in patients with COVID-19

Bleeding, thrombosis, and transfusion with two heparin anticoagulation protocols in venoarterial ECMO patients

Heparin-sparing anticoagulation strategies are viable options for patients on veno-venous ECMO

ABO blood group and risk of thromboembolic and arterial disease

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Mechanical ventilation during extracorporeal membrane oxygenation in patients with acute severe respiratory failure

The authors would like to thank Dr. Yousef Rezaei, Ms. Mandana Hosseinzadeh, and Miss Sepideh Nazari for their sincere cooperations.

The authors declare that there are no conflict of interests.

All authors collected the clinical data, drafted and revised the manuscript. AHMADI ET AL. | 5

https://orcid.org/0000-0002-9563-924XFarzaneh Dastan http://orcid.org/0000-0001-7253-4333