Abstract
Objective: To compare the characteristics, treatments and 6-month functional outcomes of patients with coronavirus disease 2019 (COVID-19) versus non-COVID-19 viral pneumonitis supported by venovenous extracorporeal membrane oxygenation (VV-ECMO).
Design: Prospective, observational cohort study in seven intensive care units (ICUs) across Australia.
Participants: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 or viral pneumonitis requiring VV-ECMO.
Results: From 30 March 2019 to 31 December 2020, 13 patients were initiated on VV-ECMO for COVID-19 and 23 were initiated for non-COVID-19 viral pneumonitis. Patients with COVID-19 were older and had a longer duration from intubation to ECMO initiation, but had similar illness severity and APACHE IV scores at the time of initiation. Overall disability, health-related quality of life, and mortality were similar, but ICU and hospital length of stay were significantly longer in patients with COVID-19.
Conclusions: Six-month functional outcomes and mortality were similar between COVID-19 and viral pneumonitis patients treated with VV-ECMO. However, length of stay was longer in COVID-19 patients, which may have resource implications.
Pandemic viral respiratory tract infections can lead to severe viral pneumonitis which is refractory to conventional intensive care unit (ICU) treatments, necessitating venovenous extracorporeal membrane oxygenation (VV- ECMO). Over the past 3 years, Australia has experienced two major viral outbreaks, including a non-coronavirus disease 2019 (COVID-19) (predominantly influenza) outbreak in 2019-2020 and the COVID-19 pandemic in 2020.1 Few studies have directly compared the patient characteristics, disease course, or long term impact and resource use of these different viral diseases in VV-ECMO patients.
We performed a multicentre, observational study using the Australian national ECMO registry (NCT03793257). We compared patients with severe COVID-19 pneumonitis who were supported by VV-ECMO with patients with non- COVID-19 (predominantly influenza) viral pneumonitis. Six- month survival, as well as disability (World Health Organization Disability Assessment Schedule [WHODAS]) and quality of life (Five-level EuroQol five dimensions questionnaire [EQ-5D-5L]) were assessed by trained, central assessors.
From 30 March 2019 to 31 December 2020, 13 patients were initiated on VV-ECMO for COVID-19 and 23 were initiated for non-COVID-19 viral pneumonitis in seven centres (Table 1). In comparison to non-COVID-19 viral pneumonitis, COVID-19 patients were older (median age, 58 [interquartile range (IQR), 56-66] v 44 [IQR, 33-54] years), but illness severity, arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2:FiO2) ratio, and driving pressure at the time of ECMO initiation were similar (Table 1). Median time from intubation to ECMO initiation was longer in patients with COVID-19 (7.4 [IQR, 3.3-14.0] v 0.7 [IQR, 0.2-4.6] days). Patients with COVID-19 also had increased duration of mechanical ventilation (30.4 v 16.7 days), ICU length of stay (45.6 v 23.8 days) and hospital length of stay (55.7 v 30.7 days) compared with viral pneumonitis patients. At 6 months, the mortality was numerically lower in the COVID-19 group (25% v 38.1%; P = 0.70) and the incidence of complications were similar. Functional outcomes at 6 months were available in 6/9 and 11/13 of the survivors respectively. Disability and health-related quality of life were similar. No patients from either group underwent lung transplantation.
Table 1.
Baseline characteristics of patients with coronavirus disease 2019 (COVID-19) or other viral pneumonitis receiving extracorporeal membrane oxygenation (ECMO)
| Overall | COVID-19 | Viral pneumonitis | P | |
|---|---|---|---|---|
| Total number of patients | 36 | 13 | 23 | |
| Age, years, median (IQR) | 50 (37-60) | 58 (56-66) | 44 (33-54) | 0.005 |
| Sex, female | 10 (27.8%) | 5 (38.5%) | 5 (21.7%) | 0.440 |
| APACHE IV, median (IQR) | 47 (33-84) | 40 (15-64) | 48 (36-86) | 0.277 |
| SOFA, median (IQR) | ||||
| Total | 9 (6-12) | 7 (5-10) | 9 (8-12) | 0.393 |
| Respiratory | 4 (4-4) | 3 (3-4) | 4 (4-4) | 0.001 |
| Coagulation | 0 (0-1) | 0 (0-0) | 0 (0-1) | 0.524 |
| Liver | 0 (0-0) | 0 (0-0) | 0 (0-1) | 0.568 |
| Cardiovascular | 3 (1-4) | 2 (1-4) | 3 (2-4) | 0.350 |
| Renal | 1 (0-2) | 0 (0-1) | 1 (0-2) | 0.135 |
| Days between ICU admission and ECMO start, median (IQR) | 5.2 (0.9-11.5) | 13.6 (7.4-16.8) | 1.8 (0.3-6.1) | 0.001 |
| Days between intubation and ECMO start, median (IQR) | 3.3 (0.4-7.3) | 7.4 (3.3-14.0) | 0.7 (0.2-4.6) | 0.006 |
| Type of support | 0.361 | |||
| VA-ECMO | 1 (2.8%) | 1 (7.7%) | 0 (0.0%) | |
| VV-ECMO | 35 (97.2%) | 12 (92.3%) | 23 (100.0%) | |
| Body mass index, kg/m2, median (IQR) | 29.9 (25.7-34.3) | 27.5 (23.9-32.7) | 30.4 (26.2-35.6) | 0.246 |
| Charlson Comorbidity Score, median (IQR) | 1 (0-2) | 2 (2-3) | 0 (0-1) | 0.002 |
| Comorbidities | ||||
| Heart failure | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | - |
| Chronic obstructive pulmonary disease | 1 (2.8%) | 0 (0.0%) | 1 (4.3%) | 0.999 |
| Diabetes | 5 (13.9%) | 4 (30.8%) | 1 (4.3%) | 0.047 |
| Chronic kidney disease | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | - |
| Cancer | 1 (2.8%) | 1 (7.7%) | 0 (0.0%) | 0.361 |
| Metastatic cancer | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | - |
| Leukaemia | 1 (2.8%) | 1 (7.7%) | 0 (0.0%) | 0.361 |
| Lymphoma | 1 (2.8%) | 0 (0.0%) | 1 (4.3%) | 0.999 |
| Clinical frailty score, median (IQR) | 3 (2-3) | 3 (3-3) | 2 (2-3) | 0.057 |
| Support before ECMO | ||||
| Invasive ventilation | 36 (100.0%) | 13 (100.0%) | 23 (100.0%) | - |
| Prone positioning | 8 (22.2%) | 1 (7.7%) | 7 (30.4%) | 0.213 |
| Recruitment manoeuvre | 5 (16.7%) | 1 (11.1%) | 4 (19.0%) | 0.999 |
| Neuromuscular blocking agents | 17 (48.6%) | 5 (41.7%) | 12 (52.2%) | 0.725 |
| Norepinephrine | 27 (77.1%) | 10 (83.3%) | 17 (73.9%) | 0.685 |
| Renal replacement therapy | 6 (17.1%) | 2 (16.7%) | 4 (17.4%) | 0.999 |
| Vital signs before ECMO, median (IQR) | ||||
| Temperature, °C | 36.9 (36.4-37.6) | 36.8 (36.3-37.4) | 37.0 (36.4-37.6) | 0.495 |
| Heart rate, beats/min | 96.0 (87.0-1 10.5) | 95.5 (89.5-106.5) | 100.0 (85.0-116.5) | 0.626 |
| Mean arterial pressure, mmHg | 76.0 (69.0-82.5) | 81.0 (77.5-85.8) | 73.0 (68.0-81.5) | 0.081 |
| SpO2, % | 91.5 (87.2-95.8) | 91.0 (87.5-95.2) | 92.0 (87.2-95.8) | 0.610 |
| Ventilatory variables before ECMO, median (IQR) | ||||
| Tidal volume, mL/kg PBW | 5.3 (4.0-6.5) | 5.1 (4.6-5.9) | 5.6 (3.8-6.5) | 0.958 |
| Peak pressure, cmH2O | 29.0 (24.0-35.0) | 27.5 (23.5-31.0) | 31.0 (25.0-36.0) | 0.209 |
| PEEP, cmH2O | 12.0 (10.0-15.0) | 12.0 (10.0-15.0) | 12.0 (10.0-15.0) | 0.880 |
| Total respiratory rate, breaths/min | 22.0 (16.5-26.0) | 26.0 (23.0-30.0) | 20.0 (12.0-23.0) | 0.004 |
| Driving pressure, cmH2O | 16.0 (10.0-24.0) | 15.0 (11.0-19.5) | 19.0 (10.0-24.0) | 0.274 |
| FiO2, % | 100.0 (80.0-100.0) | 100.0 (80.0-100.0) | 100.0 (85.0-100.0) | 0.970 |
| Laboratory tests before ECMO, median (IQR) | ||||
| pH | 7.24 (7.13-7.34) | 7.28 (7.20-7.34) | 7.20 (7.12-7.34) | 0.358 |
| PaO2:FiO2 | 83.0 (67.0-1 15.0) | 87.9 (67.0-108.3) | 83.0 (67.0-1 18.0) | 0.808 |
| PaCO2, mmHg | 67.0 (52.0-76.0) | 70.5 (55.7-76.0) | 66.0 (52.0-75.0) | 0.640 |
| Lactate, mmol/L | 1.3 (0.9-1.7) | 1.6 (1.2-1.7) | 1.2 (0.9-1.7) | 0.301 |
| Hospital outcomes | ||||
| Complications during ECMO | ||||
| ► Renal replacement therapy | 23 (65.7%) | 8 (61.5%) | 15 (68.2%) | 0.726 |
| ► Pneumothorax | 3 (8.3%) | 2 (15.4%) | 1 (4.3%) | 0.539 |
| ► Cardiac arrest | 3 (8.3%) | 0 (0.0%) | 3 (13.0%) | 0.288 |
| ► Major bleeding | 8 (22.2%) | 5 (38.5%) | 3 (13.0%) | 0.107 |
| ► Pulmonary embolism | 1 (2.8%) | 1 (7.7%) | 0 (0.0%) | 0.361 |
| ► CNS diffuse ischaemia | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | - |
| ► CNS bleeding | 2 (5.6%) | 0 (0.0%) | 2 (8.7%) | 0.525 |
| ► Lung infection | 17 (47.2%) | 5 (38.5%) | 12 (52.2%) | 0.502 |
| ► Thrombosis of ECMO circuit | 1 (2.8%) | 0 (0.0%) | 1 (4.3%) | 0.999 |
| ► Thrombosis of ECMO filter | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | - |
| Duration of ECMO, days, median (IQR) | 9.8 (6.7-15.8) | 14.8 (8.3-23.4) | 9.1 (7.0-12.7) | 0.301 |
| Duration of ventilation, days, median (IQR) | 18.8 (13.3-46.0) | 31.2 (17.1-54.0) | 16.7 (10.1-31.0) | 0.043 |
| ICU length of stay, days, median (IQR) | 30.4 (19.5-50.1) | 48.0 (33.0-106.1) | 23.8 (15.8-35.0) | 0.004 |
| ► In survivors, days, median (IQR) | 34.6 (24.2-56.3) | 49.9 (41.8-123.9) | 27.0 (18.9-35.0) | 0.008 |
| Hospital length of stay, days, median (IQR) | 40.5 (23.7-59.2) | 57.2 (48.9-143.9) | 30.7 (19.0-46.1) | 0.005 |
| ► In survivors, days, median (IQR) | 49.0 (32.1-78.2) | 66.6 (55.0-169.9) | 36.1 (21.2-46.1) | 0.006 |
| ► ICU mortality | 11 (31.4%) | 3 (23.1%) | 8 (36.4%) | 0.478 |
| ► Hospital mortality | 11 (32.4%) | 3 (23.1%) | 8 (38.1%) | 0.465 |
| ► 180-day mortality | 11 (33.3%) | 3 (25.0%) | 8 (38.1%) | 0.703 |
| Long term outcomes at 6 months | ||||
| WHODAS score, %, median (IQR) | 22.9 (4.2-50.0) | 32.3 (8.3-56.2) | 22.9 (3.1-42.7) | 0.392 |
| ► Disability | 8 (47.1%) | 3 (50.0%) | 5 (45.5%) | 0.999 |
| ► New disability | 8 (61.5%) | 4 (66.7%) | 4 (57.1%) | 0.999 |
| EQ-5D-5L utility score, median (IQR) | 0.8 (0.4-0.8) | 0.6 (0.3-0.8) | 0.8 (0.7-0.9) | 0.339 |
APACHE = Acute Physiology and Chronic Health Evaluation; CNS = central nervous system; EQ-5D-5L = Five-level EuroQol five dimensions questionnaire; FiO2 = fraction of inspired oxygen; ICU = intensive care unit; IQR = interquartile range; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; PEEP = positive end-expiratory pressure; PBW = predicted body weight; SOFA = Sequential Organ Failure Assessment; SpO2 = oxygen saturation measured by pulse oximetry; VA-ECMO = veno-arterial extracorporeal membrane oxygenation; VV-ECMO = venovenous extracorporeal membrane oxygenation; WHODAS = World Health Organization Disability Assessment Schedule.
This nationwide study highlights important demographic and long term outcome differences in VV-ECMO patients with different types of viral pneumonitis. Although the patients had similar illness severity at baseline, COVID-19 patients were initiated on ECMO much later following intubation. Traditionally, VV-ECMO outcomes have been worse for this late initiation group,2 and recent COVID-19 Extracorporeal Life Support Organization (ELSO) guidelines suggest late (> 7 days mechanical ventilation) initiation is a relative contraindication.3 However, we found that 6-month mortality and disability were comparable for COVID-19 and viral pneumonitis patients, and compared favourably with other recently published data,4 suggesting that acceptable survival can occur in this late initiation group. In contrast, ECMO duration, ICU and hospital length of stay were longer with COVID-19, which may have significant resource implications during the COVID-19 pandemic and in periods of ICU strain. The findings of this study are preliminary, with small patient numbers and relatively few patients who were proned, and reflect a health care system that was not overwhelmed.
In conclusion, our data show that 6-month survival, disability, and quality of life for COVID-19 were similar to other viral pneumonitis, despite ECMO being initiated much later. However, the prolonged length of stay for these patients may have significant resource implications. These findings require further validation in larger datasets.
Competing interests
All authors declare that they do not have any potential conflict of interest in relation to this manuscript.
Acknowledgements
The EXEL Investigators are: Carol L Hodgson,1,2,3,4 Alisa M Higgins,1,2 Michael J Bailey,1,2,4 Stephen Bernard,2 Bentley J Fulcher,1,2 Denise Koe,2 Natalie J Linke,1,2 Shannah Anderson,1 Stephen Bernard,3 Jasmin V Board,3 Daniel Brodie,5 Heidi Buhr,6 Aidan JC Burrell,1,2,3 David J Cooper,1,2,3 Eddy Fan,7 John F Fraser,8,9 David J Gattas,6 Ingrid K Hopper,2 Sue Huckson,10 Edward Litton,11 Shay P McGuinness,1,12,13 Priya Nair,14 Neil Orford,15,16 Rachael L Parke,1,12,13,17 Vincent A Pellegrino,3 David V Pilcher,1,3 Jayne Sheldrake,3 Benjamin AJ Reddi,18 Dion Stub,2,3 Tony V Trapani,1,2 Andrew A Udy,1,2,3 Ary Serpa-Neto1,4
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1.
Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
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2.
School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
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3.
Intensive Care Unit, Alfred Hospital, Melbourne, VIC, Australia.
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4.
University of Melbourne, Melbourne, VIC, Australia.
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5.
Department of Medicine and Center for Acute Respiratory Failure, Columbia University College of Physicians and Surgeons/New York-Presbyterian Hospital, New York, NY, USA.
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6.
Intensive Care Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
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7.
Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
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8.
University of Queensland, Brisbane, QLD, Australia.
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9.
Critical Care Research Group, Adult Intensive Care Society, Prince Charles Hospital, Brisbane, QLD, Australia.
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10.
Australian and New Zealand Intensive Care Society, Melbourne, VIC, Australia.
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11.
Intensive Care Unit, Fiona Stanley Hospital, Perth, WA, Australia.
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12.
Medical Research Institute of New Zealand, Wellington, New Zealand.
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13.
Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand.
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14.
Intensive Care Unit, St Vincent’s Hospital, Sydney, NSW, Australia.
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15.
Intensive Care Unit, University Hospital Geelong, Geelong, VIC, Australia.
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16.
School of Medicine, Deakin University, Geelong, VIC, Australia
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17.
Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
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18.
Intensive Care Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
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