key: cord-032891-pvijxcgi
authors: Zhang, Joe; Merrick, Blair; Correa, Genex L.; Camporota, Luigi; Retter, Andrew; Doyle, Andrew; Glover, Guy W.; Sherren, Peter B.; Tricklebank, Stephen J.; Agarwal, Sangita; Lams, Boris E.; Barrett, Nicholas A.; Ioannou, Nicholas; Edgeworth, Jonathan; Meadows, Christopher I.S.
title: Veno-venous Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019: A Case Series
date: 2020-09-25
journal: ERJ Open Res
DOI: 10.1183/23120541.00463-2020
sha: 
doc_id: 32891
cord_uid: pvijxcgi

RATIONALE: The use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) in severe hypoxaemic respiratory failure from Coronavirus disease 2019 (COVID-19) has been described, but reported utilisation and outcomes are variable, and detailed information on patient characteristics is lacking. We aim to report clinical characteristics, management, and outcomes of COVID-19 patients requiring VV-ECMO, admitted over 2 months to a high-volume UK centre. METHODS: Patient information, including baseline characteristics and clinical parameters, was collected retrospectively from electronic health records for COVID-19 VV-ECMO admissions between 3rd March and 2nd May 2020. Clinical management is described. Data are reported for survivors and non-survivors. RESULTS: We describe 43 consecutive patients with COVID-19 who received VV-ECMO. Median age was 46 years [IQR 35.5–52.5], 76.7% were male. Median time from symptom onset to VV-ECMO was 14 days [IQR 11–17.5]. All patients underwent computed tomography imaging, finding extensive pulmonary consolidation in 95.3%, and pulmonary embolus in 27.9%. 79.1% received immunomodulation with methylprednisolone for persistent maladaptive hyperinflammatory state. Vasopressors were used in 86%, and 44.2% received renal replacement therapy. Median duration on VV-ECMO was 13 days [IQR 8–20]. Fourteen patients died (32.6%) and 29 survived (67.4%) to hospital discharge. Non-survivors had significantly higher d-dimer (38.2 versus 9.5 mg·L(−1), Fibrinogen Equivalent Units; p=0.035) and creatinine (169 versus 73 umol·L(−1); p=0.022) at commencement of ECMO. CONCLUSIONS: Our data supports the use of VV-ECMO in selected COVID-19 patients. The cohort was characterised by high degree of alveolar consolidation, systemic inflammation, and intravascular thrombosis.

A significant cohort of patients with Coronavirus disease 2019 (COVID-19) go on to develop severe respiratory failure, requiring critical care admission. Reports have described the use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) in a subset of critically ill patients, with utilisation ranging from 11% to 32% (1) (2) (3) . VV-ECMO is indicated for patients with potentially reversible, refractory, lifethreatening hypoxaemia or hypercapnia, or in patients where acceptable oxygenation or decarboxylation can be obtained only with injurious ventilatory settings. While VV-ECMO was associated with improved outcome during the H1N1 influenza pandemic (4, 5) , COVID-19 demonstrates features unique from other respiratory infections and early case-series have reported high mortality in patients on ECMO (6) (7) (8) .

Given the lack of detailed information about patient characteristics and their clinical course, balanced with the need for judicious use of resources in the context of a pandemic, it is important to understand the role of VV-ECMO in COVID-19. We aim to describe, in detail, the clinical characteristics, management and outcomes of COVID-19 VV-ECMO patients from a high-volume UK ECMO centre, over a twomonth period of the pandemic.

All COVID-19 patients admitted for VV-ECMO to Guy's and St Thomas' NHS Foundation Trust (GSTFT) in London, over a two-month period (3rd March 2020 to 2nd May 2020) covering the peak of the pandemic, are included. Suitability for VV-ECMO was assessed in line with UK national commissioning criteria (9) , requiring a lung injury (Murray) score ≥3 (10) , or uncompensated hypercapnic acidosis with pH <7.2. National criteria were adapted for the COVID-19 pandemic on the 10 th of April 2020 (11) to include clinical frailty scale ≤3 (12) , the use of the Respiratory ECMO Survival Prediction (RESP) score (13) to aid pre-ECMO decision-making (with RESP score ≤3 requiring agreement between at least two centres), and an exclusion of "refractory multi-organ failure". At the time of this series, detection of SARS-CoV-2 RNA on nose and throat swabs or bronchoalveolar lavage (BAL) using multiplexedtandem polymerase chain reaction technology for detection of 2 gene targets, ORF 1a and ORF 8 (AusDiagnostics, Mascot, Australia), remained gold standard. All patients, at point of referral, had either laboratory confirmed or clinically suspected COVID-19 pneumonia; four patients without a positive result at time of referral subsequently tested positive from admission samples at GSTFT.

GSTFT is a national VV-ECMO centre commissioned to provide regional ECMO retrieval and provision (9) . At the start of the pandemic, GSTFT ECMO capacity was doubled through adaptation of each bedspace to accommodate two patients on ECMO. Patients were retrieved from referring hospitals via a previously described standard pathway (14) , with no deviation in practice aside from use of recommended personal protective equipment. Standard GSTFT practice is bifemoral percutaneous cannulation at the referring hospital, and use of Maquet Cardiohelp (Maquet, Rastatt, Germany) consoles. Following retrieval, all patients underwent computed tomography (CT) imaging of head, thorax (including CT pulmonary angiogram), abdomen and pelvis. Lung recruitment CT imaging at ventilator pressures of 5 cmH 2 O and 45 cmH 2 O were performed, unless pneumothorax was detected on initial scan or pulmonary air leak was suspected, to assess lung recruitment potential and delineate underlying lung parenchyma (15) . Diagnostic bronchoscopy and BAL for bacterial culture, viral and SARS-CoV-2 PCR was performed on all patients within the first 24 hours. Patients without haemorrhagic complications were anticoagulated with unfractionated heparin infusion, targeting anti-Xa levels (0.3-0.7 UI/mL).

Patients were ventilated with protective lung parameters. Mechanical ventilation was generally initiated using standardised settings: PEEP 10-15 cmH 2 O, tidal volume 2-4 ml/kg of predicted body weight provided that driving pressure (plateau minus PEEP total) could be kept at 10 cmH 2 O, and plateau pressure < 25 cmH 2 O. Initial respiratory rate was generally maintained at 10 breaths/minute to limit overall mechanical power (15) . In patients with high potential for lung recruitmentas Patients received a course of broad-spectrum antibiotics on arrival, targeted to known microbiology where possible. A subset of patients with failure to progress and signs of a sustained hyperinflammatory state (fevers, persistently elevated Creactive protein and/or ferritin, sustained organ dysfunction and hypoxaemia), in the absence of untreated active infection (bacteria or fungal species detected on blood culture and BAL, low procalcitonin and galactomannan), were treated with low dose methylprednisolone regimens of 1-2mg/kg/day for 5-7 days, with halving in dose every 5-7 days, similar to published protocol (16) . This dosing regimen was chosen for its relative safety profile (17, 18) . Patients with persistent hyperinflammatory disease behaviour despite corticosteroids, or those with an "H score" greater than 169 suggesting secondary haemophagocytic lymphohistiocytosis (19, 20) were considered for treatment with the IL-1 receptor antagonist anakinra (21, 22) . Patients with persistent hypoxaemia and radiological abnormality despite low dose corticosteroids, or patients who demonstrated early fibrosis on CT, were treated with high dose "pulsed" methylprednisolone at doses of 1g for 3 days, followed by 1mg/kg per day, followed by a weaning regimen. Treatments were given in consultation with local lung inflammation specialists.

Patients generally remained paralysed for an initial 24 hours, particularly if strong inspiratory efforts persisted despite adequate sedation, or if asynchronies due to deep sedation were noted (e.g. reverse triggering). Daily sedation wean was then undertaken in stable patients to maximise wakefulness. A specialist physiotherapy team assessed patients on a daily basis for both secretion clearance, and early rehabilitation. Ventilation weaning was based on daily assessment of lung mechanics, as well as ability to spontaneously ventilate without injurious tidal volumes, respiratory rate and inspiratory effort (including measurements of P0.1 -100ms airway occlusion pressure), that might contribute to patient self-inflicted lung injury (P-SILI). Criteria for decannulation from VV-ECMO in this cohort included maintained fractional inspired oxygen < 0.5 and non-injurious ventilatory effort, with ECMO sweep gas turned off for at least 24 hours. The full protocol of weaning from VV-ECMO is described and available (23) .

Data was collected retrospectively from electronic records, including the IntelliVue Clinical Information Portfolio (Phillips, Eindhoven, The Netherlands). Pre-ECMO data were obtained from ECMO referral systems(24), paper records, or direct interview with members of retrieval teams. RESP score was calculated at the time of referral. 

Forty-three patients with COVID-19 were accepted and admitted for VV-ECMO based on the listed criteria, out of 215 patients referred to GSTFT during the study 11 -18] days, and median from invasive ventilation to VV-ECMO was 5 days [2 -6] .

The Acute kidney injury (creatinine ≥105umol/L) was a common feature (21 patients, 48.8%). Data is shown in table 2.

Twenty-nine patients (67.4%) were successfully decannulated from VV-ECMO and survived until hospital discharge. Twelve (27.9%) patients died on ECMO, and two 

The mortality described in this VV-ECMO series (14 of 43, 32.6%) is lower than in early descriptions. Patients exhibited particular characteristics including poor lung compliance, persistent hyperinflammation, and high incidence of thrombosis.

Survival in this series is comparable to more recent data from the USA(25) and

France (26) . Since the study period, a further 13 patients have completed VV-ECMO at GSTFT, with overall survival to ICU discharge at 71.4%.

The pattern of disease seen in our cohort has been previous described. Exudative lung disease with poor compliance (as described by Gattinoni et al(27) ), persistent hyperinflammation (28, 29) , and increased thrombosis incidence may demonstrate a particular phenotype that defines a later stage of the disease process. Median ferritin and d-dimer seen at ECMO initiation were comparable to values seen after two weeks in a cohort of non-surviving hospitalised patients (30) . A majority of our patients were given immunomodulation (19) after risks of immunosuppressing critically ill patients (31) The incidence of PE (27.9%) was substantially higher than in pre-COVID-19 (9.6%) in the same centre (33) , carrying substantial morbidity in our cohort with RV dysfunction in 50%. Cannula-related thrombosis rates (54.8%) were greater than baseline prevalence (34) , and ECMO membrane complication rate was similarly high.

Thrombosis risk is a known entity in severe COVID-19 (35) , but adjusted anticoagulation targets must be balanced against higher risk of haemorrhagic complication in ECMO (36) , the cause of multiple complications and one death in our cohort.

At time of writing, no published literature specifically addresses secondary or coinfection in COVID-19 ECMO. These individuals may represent a distinct cohort microbiologically. The unusual predominance of Klebsiella spp has been seen elsewhere, as has Candida spp (37, 38) , but remains a focus of further analysis in GSTFT regarding infection control consequences of doubling bedspace usage.

Admission procalcitonin was elevated in all patients, but significantly greater procalcitonin in the non-survivor group may have limited earlier use of steroids.

Reactivation or flares of chronic viral infections including CMV must also be considered, especially in those receiving immunomodulation.

Following new commissioning criteria in the UK, the threshold for acceptance of patients onto VV-ECMO has been reinforced by the inclusion of the RESP score.

This predictive score is validated in patients already on ECMO(13, 39), but not as a pre-ECMO decision tool. The RESP score was one component of a multi-tool assessment process when deciding which patients should be offered VV-ECMO, and cases with low RESP scores were discussed with a second centre if ECMO was felt to be indicated. Validation of this tool in the UK ECMO population may help guide future usage.

This series has the inherent limitations of a single-centre study, conducted in a wellresourced and experienced centre, during the early stages of our understanding in a new disease. It is likely that aspects of management will differ over time and between centres, as our understanding of how to treat particular phenotypes improves in any future pandemic waves.

This case series suggests that VV-ECMO, when offered to patients with COVID-19 respiratory failure refractory to conventional ventilatory management, can be associated with a favourable outcome. In COVID-19 patients with severe respiratory failure, early consultation with an ECMO centre and joint decision-making on suitable support modality is a key strategy. [8 -20] Causes of death (n (%)) -On ECMO 6 (42.9)

-Full active treatment* -2 (33. 

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