key: cord-0748191-akhrdj0n authors: Wen, Jun-Lin; Sun, Qi-Zhe; Cheng, Zhou; Liao, Xiao-Zu; Wang, Li-Qiang; Yuan, Yong; Li, Jian-Wei; Hou, Liu-Sheng; Gao, Wen-Jun; Wang, Wei-Jia; Soh, Wei-Yan; Li, Bin-Fei; Ma, Da-Qing title: Extracorporeal membrane oxygenation for coronavirus disease 2019-associated acute respiratory distress syndrome: Report of two cases and review of the literature date: 2021-03-16 journal: World J Clin Cases DOI: 10.12998/wjcc.v9.i8.1953 sha: 175098e30a1965b4d90d6f1c72e4ca442c6be3ea doc_id: 748191 cord_uid: akhrdj0n BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is a worldwide pandemic. Some COVID-19 patients develop severe acute respiratory distress syndrome and progress to respiratory failure. In such cases, extracorporeal membrane oxygenation (ECMO) treatment is a necessary life-saving procedure. CASE SUMMARY: Two special COVID-19 cases—one full-term pregnant woman and one elderly (72-year-old) man—were treated by veno-venous (VV)-ECMO in the Second People’s Hospital of Zhongshan, Zhongshan City, Guangdong Province, China. Both patients had developed refractory hypoxemia shortly after hospital admission, despite conventional support, and were therefore managed by VV-ECMO. Although both experienced multiple ECMO-related complications on top of the COVID-19 disease, their conditions improved gradually. Both patients were weaned successfully from the ECMO therapy. At the time of writing of this report, the woman has recovered completely and been discharged from hospital to home; the man remains on mechanical ventilation, due to respiratory muscle weakness and suspected lung fibrosis. As ECMO itself is associated with various complications, it is very important to understand and treat these complications to achieve optimal outcome. CONCLUSION: VV-ECMO can provide sufficient gas exchange for COVID-19 patients with acute respiratory distress syndrome. However, it is crucial to understand and treat ECMO-related complications. Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly evolved into a worldwide pandemic. To date, there are more than 33 million confirmed cases and 1 million deaths globally [1] . It has been shown that the lungs are the most affected organ, and many COVID-19 patients developed acute respiratory distress syndrome (ARDS) during their illness [2, 3] . Extracorporeal membrane oxygenation (ECMO) is a mechanical pump-assisted device that provides circulatory and respiratory support for patients experiencing cardiopulmonary failure. As a life-supporting intervention, ECMO is recommended by the World Health Organisation's interim guidance as a treatment for patients with refractory hypoxemia despite conventional ventilation support [4] . Here, we report two special COVID-19 patients-one full-term pregnant woman and one elderly (72-year-old) man-whose lives were saved by veno-venous (VV-)ECMO support in the Second People's Hospital of Zhongshan, Guangdong Province, China. Case 1: The patient reported symptoms having started 4 d prior, coinciding with a travel back to Zhongshan from Wuhan on January 25, 2020. She reported having attended regular antenatal checks throughout her pregnancy, with all examination results having been normal. Within 6 h of admission to the Xiaolan People's Hospital, she developed severe hypoxia and septic shock. She was intubated and sedated for administration of mechanical ventilation (MV). An emergency caesarean delivery was carried out at bedside, and a live male was delivered. The infant weighed 2700 g and had an Apgar score of 1 at 1 min immediately after delivery. Cord blood tests indicated severe acidosis, hypoxemia, and potential cardiac damage. The infant died on the same day, despite receipt of active care. The patient's family refused a postmortem examination, precluding determination of a definitive cause of death (i.e., viral infection and/or hypoxia before birth). As the mother's condition was extremely unstable, she was transferred to the Second People's Hospital of Zhongshan the day after delivery, in the early morning. Case 2: The patient's symptoms started 1 wk before presenting to hospital. Case 1: The patient had previous good health. The patient had a long-term history of hypertension (20 years) and had undergone percutaneous coronary intervention (PCI) for left main and three-vessel coronary artery disease 5 years prior. Case 1: The patient declared no remarkable family medical history. Case 1: Upon admission to the Second People's Hospital of Zhongshan, the patient was placed on assisted MV [positive end-expiratory pressure (PEEP) of 15 cmH 2 O] under mild sedation. Intravenous norepinephrine was administered at 0.8 μg/kg/min. The patient's vital signs at admission were: Body temperature, 36.3 °C; pulse, 150 beats/min; and respiratory rate, 25 breaths/min. Her blood pressure was 122/79 mmHg and peripheral capillary oxygen saturation was 96.4%. Chest auscultation revealed coarse crackles in the left inferior lobe. No pathologic heart sound was detected by cardiac auscultation. The patient's vital signs at admission were body temperature of 37.5 °C, pulse of 98 beats/min, and respiratory rate of 20 breaths/min. His blood pressure was 129/71 mmHg. Chest auscultation detected crackles in both lungs. There was no pathologic sound detected from cardiac auscultation. Case 1: Routine blood tests administered at admission gave the following results: White blood cell count, 6.8 × 10 9 /L (normal range: 4-10 × 10 9 /L); lymphocytes, 14% (normal range: 17%-48%); neutrophils, 83.2% (normal range: 43%-76%); haemoglobin, 110 g/L (normal range: 110-150 g/L); red blood cell count, 3.48 × 10 12 /L (normal range: 3.5-5.5 × 10 12 /L); and platelet count (PLT), 160 × 10 9 /L (normal range: 100-300 × 10 9 /L). Biochemical tests showed high-level aspartate aminotransferase (AST) (190. 6 SARS-CoV-2 test, from nasopharyngeal swab specimen, was positive. Case 1: Chest X-ray showed large patchy shadows in bilateral lungs ( Figure 3A ). Fibreoptic bronchoscopy detected massive frothy sputum. Case 2: Chest X-ray showed infiltrates in bilateral lungs ( Figure 4A ). A chest computed tomography (CT) scan demonstrated ground-glass opacities and consolidation in bilateral lungs. The representative upper, middle, and lower transverse chest CT images showed multiple ground glass shadows in both lungs (day 3; Figure 5 ). Case 1: COVID-19 pneumonia, ARDS, septic shock, septic cardiomyopathy, multiple organ dysfunction syndrome, and post-caesarean condition. Case 2: COVID-19 pneumonia, post-PCI condition, and hypertension. In consideration of her worsening hypoxemia despite maximum conventional support, VV-ECMO support was applied by the Zhongshan People's Hospital ECMO team. The ECMO circuit was established through the internal jugular vein and femoral vein percutaneously. The blood flow setting ranged from 2.5-3.5 L/min during the period of ECMO support. The patient's respiratory status improved in the first 10 d, with PaO 2 /FiO 2 ratios raising from 62 to 226. Considering her needs of prolonged MV after ECMO, a tracheostomy was performed on the day 10 of ECMO support. Surgical bleeding occurred during the operation, and the use of heparin was temporarily halted while a debridement was performed, which successfully controlled the bleeding. Between days 10 and 16 of the ECMO support, her condition worsened again, with PaO 2 /FiO 2 falling to 65. Blood measurements showed a marked increase of NT-proBtype natriuretic peptide (NT-proBNP) (reaching a maximum of 7267 pg/mL on day 14; To support her right ventricle function, the fluid management, ECMO perfusion, and PEEP were optimised. Meanwhile, to avoid potential hepatotoxicity, the use of imipenem cilastatin sodium was discontinued and replaced with piperacillin/ tazobactam. The use of vancomycin and voriconazole was also paused. Over the next week, the patient's condition improved gradually. She demonstrated sufficient oxygenation (PaO 2 /FiO 2 raised to 370), partial recovery of lung function (tidal volume > 6 mL/kg in the condition of PEEP < 10 cmH 2 O and P peak < 28 cmH 2 O), and improved chest radiography findings ( Figure 3B ). Blood tests showed that the levels of organ damage biomarkers were decreased remarkably. Case 2: Treatments applied since admission were mainly supportive, concomitant with antiviral treatment (Figure 8 ). However, after 11 d, on February 20, 2020, the patient's condition worsened. He became severely hypotensive, requiring vasoactive support (norepinephrine at 0.15 mg/kg/min). Arterial blood gas analysis revealed severe hypoxemia and respiratory alkalosis (pH, 7.49; PaO 2 , 52 mmHg; PaCO 2 , 31 mmHg). The next day, intermittent non-invasive ventilation was initiated, but the patient complained of a sense of suffocation. His arterial blood gas parameters were pH of 7.50, PaO 2 of 71 mmHg, and PaCO 2 of 32 mmHg. Since his respiratory status did not improve and due to his intolerance of the intermittent non-invasive ventilation, MV was applied (BIPAP; FiO 2 , 1 L/L; PEEP, 15 cmH 2 O). On February 22, 2020, the patient's condition deteriorated, with worsening of arterial blood gas parameters (pH, 7.29; PaCO 2 , 62 mmHg; PaO 2 , 65 mmHg). Failure of the conventional therapies to improve the patient's condition led to a decision to apply VV-ECMO support. During the first 2 d of ECMO support, the patient's haemodynamics were stable and oxygenation was improved (Figure 9 ). Over the next 10 d, however, he developed bleeding and thrombosis. The posterior pharyngeal wall was accidentally injured during sputum suctioning, which caused repeated bleeding. A chest drain was inserted to address right-sided pleural effusion (approximately 7 cm on B-scan ultrasonography); the next day yielded a total drainage volume of 1500 mL blood. As thrombi were found in the ECMO canula, the ECMO circuit was replaced. The combination of bleeding and thrombi caused difficulty in regulating anticoagulation. March 16, 2021 Volume 9 Issue 8 On day 18 of ECMO support, the decision was made to perform a tracheostomy, in recognition of the need for prolonged ventilation support after weaning-off of ECMO, with the condition of reducing heparin and applying normal plasma transfusion and cryoprecipitate. No significant bleeding occurred during the surgery. The continuation of antiviral therapy, vasoactive drugs, CRRT, anti-inflammation therapy, steroid therapy, and plasmapheresis facilitated a gradual improvement in the patient's status. Cardiac function stabilised, with decreased level of BNP (from 6925 to 1957 pg/mL; normal range: < 125 pg/mL). Chest X-ray showed decreased infiltrates in bilateral lungs ( Figure 4B ). On March 26, 2020, the patient was successfully weaned from VV-ECMO, after 33 d on ECMO. Unfortunately, following the weaning-off, the circulatory status became extremely unstable and increased levels of vasoactive drugs, sedatives, analgesics, and muscle relaxants were required. Over the next 10 d, the patient's condition continued to deteriorate further. Myelosuppression developed and blood tests revealed leukopenia, thrombocytopenia, and increased levels of inflammatory biomarkers. Therapy with recombinant human granulocyte colony-stimulating factor, γ-globulin, and plasmapheresis was initiated. Case 1: The VV-ECMO therapy was stopped 21 d after ECMO application. The patient's chest X-ray was much improved, prompting weaning from MV after 36 d of such. A chest CT scan on day 40 showed absorption of inflammatory lesions compared to day 30 ( Figure 10 ). Her SARS-CoV-2 nucleic acid test result became negative after 40 d of admission (Figure 11 ). The patient was discharged from hospital to home, with normal vital signs and laboratory tests, after 46 d of admission. SARS-CoV-2 nucleic acid test became negative ( Figure 12 ). However, he had developed pulmonary fibrosis and a wide area of mucoid impaction in small airways, along with inspiratory muscle weakness. A CT scan showed diffuse ground glass opacities and honeycombing in both lungs, indicating the development of pulmonary fibrosis (day 51; Figure 5 ). As such, he remained on ventilatory support and (of the time of writing this report) may require a lung transplantation. ECMO is a life-supporting intervention, whereby an external mechanical pump collects venous blood and performs gas-exchange through an oxygenator. ECMO has been used in patients with severe ARDS for decades [5] . Since the outbreak of the COVID-19 pandemic, there has been increased usage of ECMO in supporting COVID-19 patients as an ultimate treatment to sustain their lives [6] . The advantage of ECMO in COVID-19 patients is that it maintains the oxygen supply while providing a time window for the lungs to rest and recover. However, as a highly invasive treatment, ECMO itself is associated with many life-threatening complications, such as cardiac failure, renal failure, bleeding, thrombosis, and infection. Therefore, efforts to and experience in preventing and treating ECMO-related complications are very important. In this report, we present two COVID-19 patients who were supported by ECMO. After admission, both patients experienced a rapid deterioration of their respiratory function, with a decrease of PaO 2 from 91 mmHg to 62 mmHg in the female patient and 150 mmHg to 65 mmHg in the male patient within 24 h under ventilation with FiO 2 more than 600 mL/L. Of interest, the man (case 2) experienced various fluctuations of PaO 2 /FiO 2 ratios throughout the course of ECMO, much more so than those experienced by the woman (case 1), indicating that the outcome may not be optimal ( Figure 13 ). As both patients developed severe hypoxemia despite maximum conventional ventilation support, VV-ECMO support was applied. There was an immediate increase in PaO 2 /FiO 2 ratios after the initiation of ECMO, indicating the advantage of VV-ECMO for improving oxygenation in severe COVID-19 cases. In fact, the rapid deterioration experienced, also known as the "second week crash", has been presented in multiple previous studies as a feature of COVID-19 [7] [8] [9] [10] . It is characterized as a phenomenon that occurs 7-8 d after the initial symptom onset, with some COVID- 19 patients' symptoms progressing suddenly from mild to severe. A recent immunology study revealed that this unique pattern of clinical course is associated with over-production of inflammatory factors [11] . Overall experience suggests that early application of anti-inflammatory therapies may relieve this life-threatening course, making it worthwhile to investigate its mechanism and optimal strategies in the future. In our case series, the first patient was discharged from hospital with normal vital signs and laboratory tests, while the other remained in-hospital on ventilation support and may require a lung transplantation due to pulmonary fibrosis. Several factors may explain the outcome difference between these two patients. One of those factors is age. It has been shown that older people are at an increased risk of developing pulmonary fibrosis following COVID-19-induced ARDS (45.4 ± 16.9 vs 33.8 ± 10.2 years of age) [12, 13] . Similarly, retrospective studies have revealed that older patients were more prone to developing pulmonary fibrosis following SARS-or Middle East respiratory syndrome (commonly known as MERS)-induced ARDS [14] . This should be taken into consideration since ECMO is such a resource-intensive procedure and involves expensive equipment. Another possible factor is the timing of MV. For our case 1, the MV was initiated immediately after oxygen therapy failure, while for our case 2, highconcentration oxygen therapy was applied for 10 d and shortness of breath occurring over 1 d prompted MV support. Although oxygen therapy is a life-saving technique for patients with hypoxia, it has been demonstrated that continuous highconcentration oxygen therapy can cause lung injury [15] . Besides, studies have shown that the high transpulmonary pressure caused by shortness of breath can also damage the lungs [16] , which may have happened in our patient (case 2). There is probably a survival benefit to the application of MV at an earlier time for COVID-19 patients in whom oxygen therapy cannot provide a satisfactory level of oxygenation, and this needs to be investigated in the future. In addition, hospital-acquired infection may have contributed to the opposite outcomes of our patients as well. In case 1, no bacteria were detected in blood culture; in case 2, Streptomonas maltophilia was detected in blood culture after removing ECMO. This pathogen may have further aggravated the COVID-19-related inflammation in his lungs and deterioration of his pulmonary function. Acute cardiac failure is one complication of ECMO. On day 10 of ECMO support, our female patient (case 1) developed acute RVD. RVD is defined as a clinical syndrome meeting at least one of the following criteria: Acute presence of right ventricle systolic dysfunction, confirmed by echocardiography; and increase of cardiac enzymes in the absence of left ventricle and renal dysfunction and moderate to severe right ventricular strain patterns detected by electrocardiogram [17, 18] . RVD is a common complication of ARDS, with a reported incidence ranging from 30% to 56% [19, 20] ; of note, a consecutive study of 74 ARDS patients referred to ECMO found an RVD incidence of 28.6% [21] . The main direct aetiology of RVD in ARDS is right ventricle overload [22] . The most common cause of excessive right ventricle preload is fluid overload. VV-ECMO application over a long duration and high flow can also be a cause of increased right ventricle preload. As VV-ECMO provides non-pulsatile flow, it may cause a right ventricle volume overload over time [23] . Optimisations of fluid management and ECMO flow, therefore, may serve as effective ways to treat excessive right ventricle preload-related right ventricle dysfunction. On the other hand, right ventricle overloading has been associated with hypoxic/hypercarbic vasoconstriction and high PEEP setting in MV [18, 23] . Improving gas exchange and reducing PEEP may, therefore, help decrease right ventricle afterload. To prevent RVD, early diagnosis and intervention are important. There are four predictors of RVD in ARDS that have been identified recently, namely, pneumonia-caused ARDS, driving pressure of ≥ 18 cmH 2 O (calculated as the difference between plateau pressure and total PEEP), PaCO 2 of ≥ 48 mmHg, and PaO 2 /FiO 2 of < 150 mmHg [20] . As severe COVID-19 patients who require VV-ECMO are always associated with at least one of these four predictors [24] , routine electrocardiogram and echocardiographic monitoring, and early application of right ventricle protective strategies should be applied in advance. Bleeding and thrombosis are common complications of ECMO and are associated with mortality [25] [26] [27] [28] [29] . Since there is not a standard anticoagulation protocol currently available for ECMO [30] , anticoagulation management during ECMO is a substantial challenge facing clinical care providers. In our case series, case 1 experienced bleeding at the surgical site after receiving a tracheostomy. The event was well-controlled by temporarily halting the use of heparin and performance of a debridement by otolaryngologists. Case 2 developed a combination of bleeding and thrombosis in the ECMO tube system, both of which were alleviated by adjustments of the unfractionated heparin level, administration of plasma transfusion and cryoprecipitate, and replacement of the ECMO circuit. Our anticoagulation strategy involved heparin-coated circuits with standard-level unfractionated heparin infusion, titrated to an activated coagulation time (ACT) of 150-180 s. Evidence shows that COVID-19 has an association with reduced platelet count and elevations in D-dimers and fibrin-fibrinogen degradation products, indicating that this novel disease may have an impact on coagulation status. Thus, to achieve the best outcome for these patients, a more individualised anticoagulation regimen can be generated upon close monitoring of each patient's coagulation status. On the other hand, although ACT is a gold standard for monitoring anticoagulation during ECMO, multiple studies have shown that inadequate anticoagulation or bleeding can occur despite ACT monitoring [31] [32] [33] . Since bleeding and thrombosis represent such common lifethreatening complications during ECMO, introducing alternative coagulation tests, such as the anti-Xa assay and thromboelastography, can be beneficial for COVID-19 patients. Our case series showed that ECMO provided sufficient support of gas exchange for COVID-19 patients with severe respiratory failure. Nevertheless, many complications occurred during the ECMO support application, including RVD, bleeding, thrombosis, acute renal failure, respiratory muscle weakness, and suspected pulmonary fibrosis. Our experience also supports the World Health Organization's interim guidance for ECMO to be considered only in patients with refractory respiratory failure after conventional support. 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Improvement in long-term ECMO by detailed monitoring of anticoagulation: a case report We would like to express our sincere gratitude to those clinicians who made tremendous efforts towards saving lives during the COVID-19 pandemic. We want to thank the patients presented herein for giving permission to present their cases and to the unnamed patients who donated convalescent plasma.