Liberation Form Veno-Venous Extracorporeal Membrane Oxygenation For Respiratory Failure - A Scoping Review

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Liberation form veno-venous extracorporeal membrane oxygenation for respiratory

failure: a scoping review
Ricardo Teijeiro-Paradis, Tsega Cherkos-Dawit, Laveena Munshi, Niall D. Ferguson,

Eddy Fan
PII: S0012-3692(23)00897-8
DOI: https://doi.org/10.1016/j.chest.2023.06.018
Reference: CHEST 5719
To appear in: CHEST
Received Date: 4 March 2023

Revised Date: 3 June 2023
Accepted Date: 14 June 2023
Please cite this article as: Teijeiro-Paradis R, Cherkos-Dawit T, Munshi L, Ferguson ND, Fan E,
Liberation form veno-venous extracorporeal membrane oxygenation for respiratory failure: a scoping
review, CHEST (2023), doi: https://doi.org/10.1016/j.chest.2023.06.018.
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Copyright © 2023 Published by Elsevier Inc under license from the American College of Chest
Physicians.
Word count: 3167
Abstract: 218
Liberation form veno-venous extracorporeal membrane oxygenation for respiratory failure: a

scoping review
Short title: Liberation from V-V ECMO a scoping review.
Ricardo Teijeiro-Paradis1, Tsega Cherkos-Dawit1, Laveena Munshi1,2,3,4, Niall D. Ferguson1,2,3,4,5,

Eddy Fan1,2,3,4,5
1
Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
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2
Department of Medicine, University of Toronto, Toronto, ON, Canada
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3
Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON,
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Canada.
4
Department of Medicine, Division of Respirology & Critical Care, Sinai Health System and
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University Health Network, Toronto, ON, Canada.
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5
Toronto General Hospital Research Institute, Toronto, ON, Canada.
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Corresponding author:
Eddy Fan, MD, PhD
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Toronto General Hospital

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585 University Avenue, 9-MaRS-9013

Toronto, Ontario, Canada
M5G 2N2
Tel: (416) 340-5483
Email: eddy.fan@uhn.ca
ORCID:
Eddy Fan - 0000-0002-1210-9914
Niall D. Ferguson - 0000-0002-6213-5264
Laveena Munshi - 0000-0003-0551-9533
Ricardo Teijeiro-Paradis - 0000-0003-2912-4843
Statements and declarations:
Conflicts of interest, competing interest, and sources of funding:

Dr. F reports personal fees from ALung Technologies, Aerogen, Baxter, Boehringer-Ingelheim, GE
Healthcare, Inspira, and Vasomune outside the submitted work.
Dr. F reports personal fees from Baxter and Xenios, outside the submitted work.
No conflicts of interest reported for the remaining authors (RTP, TCD, LM).
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1 Abstract:
2 Background: Safe and timely liberation from veno-venous extracorporeal membrane oxygenation (V-V
3 ECMO) would be expected to reduce the duration of ECMO, the risk of complications, and costs.
4 However, how to effectively liberate patients from V-V ECMO remains understudied.
5 Research question: What is the current state of the evidence on liberation from V-V ECMO?
6 Study Design and Methods: We systematically searched for relevant publications on liberation from V-V
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7 ECMO in Medline and EMBASE. Citations were included if the manuscripts provided any of the following:
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8 criteria for readiness for liberation, a liberation protocol, and a definition of successful decannulation or
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9 decannulation failure. We included randomized trials, observational trials, narrative reviews, guidelines,
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10 editorials, and commentaries. We excluded single case reports and citations where full-text was
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11 unavailable.
12 Results: We screened 1467 citations to identify 39 key publications on liberation from V-V ECMO. We
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13 then summarized the data into 5 main topics: current strategies used for liberation, criteria used to
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14 define readiness for liberation, conducting liberation trials, criteria used to proceed with decannulation,
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15 and parameters used to predict decannulation outcomes.
16 Interpretation: Practices on liberation from V-V ECMO are heterogeneous and strongly influenced by
17 clinician preference. Additional research on liberation thresholds is needed to define optimal liberation
18 strategies and close existing knowledge gaps in essential topics on liberation from V-V ECMO.
19 Keywords: ECMO, respiratory failure, weaning, liberation
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24 Veno-venous extracorporeal membrane oxygenation (V-V ECMO) reduces mortality in patients with
25 severe acute respiratory distress syndrome (ARDS). 1-6 Due to its resource intensity, and the risk of
26 complications, patient selection has been extensively refined.7 However, how to effectively liberate
27 patients from V-V ECMO remains understudied. Timely liberation from V-V ECMO would be expected to
28 reduce duration of ECMO, risk of ECMO-related complications, and financial costs.8 Conversely,
29 premature liberation can lead to a need for recannulation, injurious mechanical ventilation and
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30 ventilator-induced lung injury (VILI).9 This trade-off between longer ECMO runs to mitigate VILI versus
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31 the exposure to ECMO-related complications as patients improve remains undefined. The aim of this
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scoping review is to outline current definitions, protocols, and strategies used to liberate patients from
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33 V-V ECMO for respiratory failure, and to highlight existing gaps in knowledge.
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34 Methods
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35 We constructed a search strategy aiming to identify publications related to liberation from V-V ECMO in
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36 patients with respiratory failure bridged to recovery in MEDLINE (1946-May 2022) and EMBASE (1947-
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37 May 2022) databases (Supplementary Appendix). The review protocol was registered in Open Science
38 Framework (OSF - https://doi.org/10.17605/OSF.IO/UH9ND). Two reviewers (RTP, TCD) independently
39 screened citations to identify relevant publications. In the event any disagreement a third reviewer (EF)
40 would make the final decision. Citations were included if the manuscript provided any of the following:
41 criteria to start liberation from V-V ECMO, a liberation protocol, and defined successful decannulation or
42 decannulation failure. We included randomized controlled trials, observational trials, narrative reviews,
43 guidelines, editorials, commentaries, and excluded single case reports and citations where full text was
44 not available.
45 Following principles used for grouping evidence on liberation from ventilation, we grouped unique
46 aspects of liberation into the following subsections: current strategies used for liberation (Table 1),
47 criteria used to define readiness for liberation (Table 1 & 3), conducting liberation trials (Table 2),
48 criteria used to proceed with decannulation (Table 1 & 3), and parameters used to predict
49 decannulation outcomes (success/failure, unsafe liberation) (Table 4). Finally, we constructed an
50 approach to liberation, guided by liberation principles from mechanical ventilation, and highlighting
51 important gaps in knowledge (Figures 2 & 3).10
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52 Weaning and liberation are often used interchangeably in the critical care literature. However, evidence
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53 from liberation from mechanical ventilation has shown that weaning – which involves gradual and slow
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reductions in support, fails to capture the true nature of separation from mechanical devices in most
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55 patients.11-13 For the purpose of this review, we introduced the following concepts: daily optimization –
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56 adjustments of support based on clinical parameters prior to considering sufficient lung recovery has
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57 been achieved (may include up-or-down-titration of ECMO), liberation – adjustments in support (ECMO
58 and mechanical ventilation) aimed at separating the patient from V-V ECMO as sufficient lung recovery
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59 has been achieved, and liberation trial – final step of liberation, where patients are trialed off ECMO
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60 (emulating spontaneous breathing trials).
61 Results
62 The search strategy yielded a total of 1467 citations. Thirty-nine citations were included for review
63 (Figure 1).2,8,9,14-49 We included 2 cross-sectional surveys describing heterogeneity in liberation
64 practices,32,43 13 reviews describing multiple aspects of liberation,16-19,22,30,36,40-42,46,47,49 2 publications
65 defining decannulation outcomes,28,48 4 citations suggesting criteria of readiness to liberate,25,29,31,38 and
66 18 publications reporting the strategy used to liberate patients from ECMO.2,8,9,14,15,20,21,23,24,26,33-
35,37,39,40,44,45
67 Within these 18 citations, 2 were randomized controlled trials,2,37 14 observational cohort
68 studies (Table 1), 8,9,15,20,21,23,24,27,33,35,39,40,44,45, and 2 case series.14,34 Eleven of these observational studies
69 had specific aims related to liberation, including testing liberation strategies, or predicting liberation
70 outcomes. 8,9,15,20,21,24,27,33,35,44,45 Only one study focused on awake-extubated V-V ECMO.23 Liberation
71 strategies used in clinical studies belonged to 2 broad groups; standardized liberation trials,8,21,27,44 and
72 clinician guided iterative reduction of ECMO support.2,9,15,20,23,24,33,35,37,39,40,45 A total of nine publications
73 (clinical studies and reviews) provided step-by-step descriptions of standardized liberation trials (Table
74 2),16,19,21,22,26,42,44,46,47 and six citations reported ventilator optimization (e.g. increase FiO2) prior to a
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75 liberation trial.8,21,27,34,35,44 Seven studies report respiratory mechanics (Table 3),9,20,21,24,27,33,44 and only 7
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76 studies considered sweep gas flow or blood flow rate prior to performing liberation trials.19-21,28,38,44,45
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77 Three citations reported predictors of readiness for liberation trials,27,46,47 3 studies explored prediction
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78 of decannulation outcome (success/failure) (Table 4)9,24,27, and 4 studies had explicit definitions of
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79 decannulation success/failure.9,28,29,48 Seven observational studies included patients with Coronavirus
80 disease-19 (COVID-19).21,23,27,33,38,44,45
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81 Discussion
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82 When attempting liberation from ECMO, clinicians may face one of 4 clinical scenarios (analogous to
83 liberation from mechanical ventilation50): Simple liberation – patients who show rapid signs of lung
84 recovery and are quickly liberated despite the liberation strategy used. Difficult liberation – patients
85 with delayed signs of lung recovery, recurrence of respiratory failure during ECMO optimization (e.g.
86 superimposed ventilator associated pneumonia), or multiple failed liberation attempts – where
87 clinicians may opt to prolong ECMO despite requiring low levels of extracorporeal support while
88 awaiting resolution of the superimposed insult or further lung recovery. Prolonged liberation – patients
89 who after prolonged ECMO support (e.g., >28 days51) still require low levels of extracorporeal support
90 to offset increased dead space ventilation – where clinicians may opt to prolong ECMO to facilitate other
91 aspects of care (e.g., physiotherapy) while awaiting recovery, decision, or transplant. Lastly, patients
92 who despite prolonged extracorporeal support will never achieve enough lung recovery to be liberated,
93 and are not candidates for lung transplantation (unweanable/one way decannulation). As with
94 mechanical ventilation, it would seem likely that duration of ECMO, and the time/number of liberation
95 attempts, are associated with outcomes.50 Observational studies have shown that the duration of
96 ventilation prior to ECMO is associated with duration of ECMO. The hypothesis is greater exposure to
97 ventilator induced lung injury, and hence longer time to lung recovery. However, due to paucity of data
98 and inconsistency in study results, the clinical implications (survival and functional outcomes) of
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99 prolonged ECMO (ELSO definition: ≥28 days) remain unknown.51-57 Duration of ECMO and/or the
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100 number of liberation attempts may be a simple way to phenotypically identify delayed lung recovery,
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101 and its association with liberation outcomes needs further exploration.
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102 Current strategies for liberation from V-V ECMO
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103 Data from cross-sectional surveys have highlighted the heterogeneity of liberation strategies used in
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104 clinical practice. 32,43 Liberation from ECMO is generally prioritized over liberation from mechanical
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105 ventilation in patients with acute respiratory failure; however, liberation from mechanical ventilation
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106 may be prioritized over liberation from ECMO in patients with chronic respiratory diseases (e.g., bridge
107 to decision or transplant). 32,43 Most ECMO centers use pressure controlled modes of ventilation, and
108 sedation early after cannulation, aiming to control of driving pressure.32,43,58,59 As patients begin to
109 recover, daily optimization of ECMO allows for sedation interruption and assisted or spontaneous
110 ventilation, preventing diaphragmatic disuse atrophy.43,58 Adherence to lung protective parameters and
111 close monitoring of excessive respiratory drive and effort is crucial to prevent VILI as patients transition
112 from controlled to spontaneous ventilation. Available strategies to monitor respiratory drive/effort
113 while optimizing ECMO and mechanical ventilation include P0.1 (pressure generated in the first 100
114 msec of a breath), POCC (pressure generated during an expiratory occlusion), Pes (esophageal pressure
115 during tidal ventilation), EADi (electrical activity of the diaphragm), and plateau pressure during
116 spontaneous breathing.27,60-63 However, limitations of these strategies include lack of widespread
117 adoption, paucity of evidence in their utility to transition/liberate patients from ECMO, and absence of
118 evidence based cutoff values to guide decision-making.
119 Historically (and in most centers that have not adopted protocolized approaches), liberation from ECMO
120 consists in clinician identification of readiness for liberation, followed by slow iterative reductions in
121 ECMO support and a liberation trial (Table 1). The duration and endpoint of the liberation trial is
122 generally left at the discretion of the treating clinician. Such non-protocolized approaches have the risk
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123 of leading to under-recognition of readiness for liberation, unsafe liberation attempts, and prolonged
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124 ECMO runs.16
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Interestingly, it was not until the recent update to the Extracorporeal Life Support Organization (ELSO)
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126 guidelines, that elements of standardization during liberation were included.46 Following these ELSO
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127 recommendations, readiness for liberation is considered once patients meet a set of clinical criteria
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128 (Table 2). Ventilatory and oxygenation reserve are then tested by gradual reductions in extracorporeal
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129 blood flow and sweep gas flow, followed by a ventilator challenge (liberalization of tidal volumes), and a
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130 liberation trial.46
131 Standardized approaches to liberation including pragmatic criteria to identify readiness for liberation,
132 liberation trials emulating spontaneous breathing trials, and criteria to start/stop a liberation trial were
133 recently shown to be safe and feasible (Table 2).8,21,44 Moreover, the adoption of standardized liberation
134 trials have led to decannulation from higher levels of ECMO support than used in routine practice,21,44
135 and reduced the duration of ECMO.8 These data may be evidence, as it happened with mechanical
136 ventilation, of the underestimation of readiness for liberation from mechanical support.
137 Criteria to define readiness for liberation
138 Observational studies and randomized controlled trials of V-V ECMO used subjective evidence of lung
139 improvement, and self-selected ventilatory parameters as defining criteria for readiness for liberation
140 (Table 1). 2,8,9,15,20,21,23-25,27,33,35,37,39,40,44,45 Such parameters are subject to heterogeneity as no clinical
141 definition of lung improvement exists, and is rather the amalgamation of data derived from fulfilment of
142 arbitrary milestones in the patients’ clinical course (e.g., resolution of the underlying disease, recovery
143 of tidal volume, etc.)(Table 3).43,49 Additional caveats include the lag between radiologic and clinical
144 improvement, and the variable influence ECMO support has on respiratory parameters. Interestingly,
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145 only few studies explicitly include the level of ECMO support as criteria to assess readiness for liberation.
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19-21,28,38,44,45
146 Using thresholds for maximal blood flow or sweep gas flow above which the patient is
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147 expected to fail may prevent liberation trials in patients in whom gas exchange parameters and
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148 respiratory mechanics are completely dependent on ECMO (low certainty of evidence – level of
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149 recommendation: expert opinion). 21,44

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150 Parameters used in clinical practice to predict sufficient lung recovery include oxygenation challenge
151 tests (Cilley test – increase FiO2 100% on the ventilator and observe the magnitude of change in PaO2)
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152 and PetCO2/PaCO2 ratio prior to a liberation trial (Table 4).27,46,47 Although the importance of dead space
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153 ventilation (PetCO2/PaCO2 ratio) as a mechanism of liberation failure has been highlighted in clinical
154 studies,24,27 the utility of both parameters as predictors of readiness for liberation was compromised by
155 the lack sensitivity and specificity when tested in validation cohorts.24,27
156 Performing ECMO liberation trials
157 After identifying patients who have achieved sufficient lung recovery, liberation trials test the capacity
158 of the patient to sustain oxygenation and ventilation off ECMO. The decision to proceed with liberation
159 trials considers current clinical conditions and clinical trajectory of the patient. If recurrent acute or
160 superimposed lung injury is suspected, liberation trials may induce lung injury due to high respiratory
161 effort.
162 Liberation trials consist in stopping gas flow through the oxygenator for hours-to-days, while keeping
163 blood flow constant to avoid circuit clotting.46 Procedures to reduce ECMO support and stop gas flow
164 vary in clinical practice and are divided in 2 groups: clinician guided iterative reductions in ECMO
165 support, and standardized liberation trials.
166 Strategies based on clinician guided iterative reductions in support are common.9,15,20,33,35,37,39,45 They
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167 rely on clinicians performing iterative adjustments of support according to blood gas values. Once the
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168 clinician considers gas exchange can be achieved without ECMO, sweep gas flow is turned off. These
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iterative reductions are time consuming and subject to considerable heterogeneity, as clinicians
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170 thresholds for adequate gas exchange or safe mechanical ventilation differ.
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171 Standardized liberation trials reduce subjectivity by protocolizing liberation (Table 2).8,19,21,26,27,42,44,46,47
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172 Such strategies use objective clinical parameters to identify patients with sufficient lung recovery.
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173 Sweep gas flow is then discontinued following standardized procedures, protocolizing the duration of
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174 the trial, and the criteria for success or failure. Standardized liberation trials are divided into 2 groups
175 (Table 2): two-step liberation trials,8,21,44 and fixed reduction in ECMO support trials.19,26,27,42,45,47 A two-
176 step liberation strategy consists in fulfilment of criteria for liberation (step 1) and discontinuation of
177 sweep gas flow from the level of support at the time eligibility criteria were met (e.g., 4 L/min to 0
178 L/min)(Step 2).21,44 A reduction in blood flow to <2.5 L/min or fraction of delivered oxygen (FdO2) to
179 <50% can been added to step 2 as a safety measure prior to stopping sweep gas flow.21 In contrast,
180 protocols following fixed reductions in ECMO support require timed stepwise reductions in sweep gas
181 flow (e.g., 33% reduction every 20 minutes) until sweep gas is discontinued.27 Although standardized
182 liberation trials are feasible, the optimal duration of the trial, and required observation time prior to
183 decannulation remains undefined.9,35
184 Mechanical ventilation during liberation form ECMO lacks standardization. Although in general
185 ventilation targets are constrained within lung protective parameters (e.g., low tidal volumes, Pplat ≤30
186 cmH2O, FiO2 ≤60 %), interventions aimed at optimizing mechanical ventilation during a liberation trial
187 are heterogeneous.8,21,27,34,35,44 Given most ECMO centers target ultralow tidal volumes during ECMO,32
188 lung collapse, atelectasis, and ventilator asynchronies are common during liberation. Ventilator
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189 challenge tests aim to counteract atelectasis and optimize ventilation prior to a liberation attempt
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190 (Table 2).46 Other reported strategies to optimize ventilation prior to liberation from ECMO include
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diuresis, bronchoscopy, and alternative modes of ventilation (neurally adjusted ventilation [NAVA] and
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192 high frequency percussive ventilation [HFPV]).14,34
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193 Awake ECMO, where liberation from mechanical ventilation is prioritized over liberation from ECMO,
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194 appears to be a safe and feasible alternative strategy.23 Patients must have evidence of lung recovery
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195 and meet criteria for extubation prior to liberation form mechanical ventilation (Table 2). After
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196 extubation, ECMO support is adjusted targeting physiologic parameters and the capacity of the patient
197 to tolerate physical activity with supplemental oxygen. Sweep gas flow is then turned off and patients
198 must ambulate prior to decannulation. Although reported outcomes using such strategy were excellent,
199 optimism for these results may be limited by the cannulation strategy used (double lumen right atrium-
200 pulmonary artery cannula) and considerably longer duration of ECMO runs.23
201 These data suggests standardized approaches are safe and feasible,8,21,27,44 and will likely become
202 standard of practice in the near future, however, results of trials comparing the effectiveness and safety
203 of standardized approaches to usual care are pending (ClinicalTrials.gov Identifier: NCT05486559).
204 Criteria to proceed with decannulation
205 Deciding whether a patient is ready to be decannulated or not takes into consideration the clinical
206 response to a liberation trial, the level of respiratory support required at trial termination, and the
207 patient’s tolerance to continuing ECMO (bleeding, hemolysis, oxygenator dysfunction). The lack of
208 guidelines defining optimal levels of respiratory support to proceed with decannulation has led to
209 considerable heterogeneity in practice (Table 3). When the level of respiratory support required to
210 sustain adequate gas exchange off ECMO results in increased risk to the patient (e.g., VILI, high FiO2,
211 need for ongoing sedation), prolonging ECMO to facilitate wakefulness, mobility, and physiotherapy
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212 while awaiting further lung recovery may be justified (low certainty of evidence – level of
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213 recommendation: expert opinion). However, prolonging ECMO on the premise of further lung recovery
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214 without providing measurable advantages in other aspects of care (e.g., wakefulness, mobility,
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215 physiotherapy) is not justified (low certainty of evidence – level of recommendation: expert opinion).
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216 The significance of elevated ventilatory requirements far out in the course of ARDS is unknown, yet, in
217 clinical practice, liberation from ECMO is frequently limited by high work of breathing.27,47 Although high
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218 work of breathing has been associated with longer ICU stay and duration of mechanical ventilation after
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219 decannulation, its impact on functional outcomes and mortality is unclear.9,33 Until stronger evidence is
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220 available, criteria to proceed with decannulation will remain heterogeneous and largely influenced by
221 clinician preferences.
222 One-way decannulation is a scenario clinicians may face, where due to poor anticipated clinical
223 outcomes (e.g., non-resolving organ failures), or particular clinical characteristics, patients are not be
224 offered recannulation in the event of decannulation failure. Clinicians may choose to further optimize
225 clinical conditions prior to attempting decannulation (e.g., additional fluid removal, physiotherapy,
226 nutrition), prolonging ECMO until they consider optimal conditions are met. However, evidence to
227 support a different approach to liberation in this group of patients is lacking.46 In addition, the decision
228 to recannulate or not has considerable ethical implications that are outside the scope of this review.
229 Anticoagulation practices during V-V ECMO are heterogeneous, 64-66 and the timing of discontinuation of
230 anticoagulation or optimization practices prior to decannulation were not discussed in included
231 references.
232 Parameters to predict decannulation outcomes
233 Similar to criteria to proceed with decannulation, the definition of successful decannulation (or failure)
234 is not consistent across studies, or clinical practice. Definitions range from survival to greater than 48
235 hours after decannulation,28,29,48 to composite endpoints including recannulation, and/or increased
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236 ventilatory or hemodynamic support within 48 hours of decannulation.9 Decannulation outcomes lack
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237 robustness, and are not patient centered outcomes.31,45 In most instances, decannulation is just a
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transition to other means of mechanical support and do not reflect the benefits or drawbacks of early
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239 liberation. Recannulation as an endpoint alone lacks reliability, as most ECMO centers may not offer a
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240 second round of ECMO in patients with complicated clinical trajectories.

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241 Current parameters associated with decannulation outcomes (unsafe liberation) include ventilatory
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242 ratio, esophageal pressure swings, tidal volume, and heart rate within 4 hours of stopping sweep gas,9
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243 higher PaCO2 and respiratory rate at decannulation,45 and platelet count at ICU admission and pre-
244 ECMO day 1 (Table 4).29 Platelet count is likely just a marker of severity of disease, and its effect
245 estimates are inflated by data driven regressions.67 However, and not surprisingly, it is factors associated
246 with dead space ventilation and not oxygenation what define current decannulation outcomes, and
247 their utility to identify mechanisms of liberation failure need to be highlighted.
248 Increased dead space ventilation is a strong driver of increased work of breathing and is common in
249 patients recovering from ARDS.68,69 Increased dead space ventilation translates into high tidal volumes,
250 respiratory rate, and efforts. In an injured or inflamed lung, these will likely induce VILI, however, their
251 impact is less clear in later stages of ARDS. Masi and colleagues showed that patients who failed
252 standard liberation criteria (facilitated weaning) and were decannulated to high intensity mechanical
253 ventilation (including proning) had similar mortality and functional outcomes compared to patients
254 decannulated after meeting liberation criteria (conventional weaning).33 Although limited by its single
255 center and retrospective nature, these data are hypothesis generating and may help guide additional
256 research.
257 Future directions:
258 Evidence generated from liberation from mechanical ventilation has shown that clinicians tend to
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259 underestimate readiness for liberation from mechanical support,11 that standardized protocols tend to
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260 be superior to clinician driven liberation,12,70 and that no single predictor preforms better than the
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liberation test itself.71 These data has helped profile current ventilator liberation strategies, and led to
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262 reductions in duration of mechanical ventilation and improved patient outcomes.72 It seems logical that
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263 liberation from V-V ECMO will follow these directions. As the number of ECMO runs continue to
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264 increase, safe and timely liberation from ECMO will become a priority. We should direct our efforts to
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265 standardize our approach to liberation and define uniform patient centered outcomes. We have
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266 constructed a clinical approach to liberation summarizing available data and highlighting current
267 knowledge gaps (Figure 2). Standardization and collecting data on escalation of support and functional
268 outcomes after removal of ECMO is key to understanding effectiveness of our liberation strategies, to
269 define decannulation success (or failure), to identify high risk phenotypes of liberation failure, and to
270 systematically approach liberation failure.
271 Limitations:
272 As the general objective was a broad outline of the current state of the evidence, we did not dwell in the
273 intricacies of some aspects of liberation. The search strategy was limited to two large databases
274 including indexed publications. Information on liberation from ECMO available in other forms of public
275 domain (e.g., blogs, podcasts, applications, videos, institutional standards of operation) were not
276 reviewed. Some references primarily included COVID-19 patients.21,23,27,33,38,44,45 Although there is no
277 evidence to support considering COVID-19 ARDS a distinct type of ARDS,73,74 the pandemic brought
278 unprecedented challenges to critical care, and liberation practices reflected in included citations may
279 not be generalizable to current or future conditions.
280 Conclusions:
281 We summarized current available evidence on liberation from V-V ECMO, highlighted the existing
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282 heterogeneity in clinical practice at multiple levels of the liberation process, proposed a potential
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283 approaching to liberation based on available data, and more importantly, made evident the
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considerable paucity of data in essential topics related to liberation, including optimal liberation
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285 strategies, and liberation trial endpoints and outcomes.
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286 Interpretation:
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287 Practices on liberation from V-V ECMO are heterogeneous and strongly influenced by clinician
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288 preference. Additional research on liberation thresholds is needed to define optimal liberation
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289 strategies and close existing knowledge gaps in essential topics on liberation from V-V ECMO.
290
291 Take Home Point:
292 Research question: What is the current state of the evidence on liberation from V-V ECMO?
293 Results: We summarized evidence on liberation identifying heterogeneity in clinical practice, paucity of
294 data to support liberation strategies, and important knowledge gaps in essential topics related to
295 liberation.
296 Interpretation: Liberation from V-V ECMO remains heterogeneous in clinical practice. Additional
297 research is needed to define optimal liberation strategies and to close knowledge gaps in essential
298 liberation topics.
299
300 Statement of authorship:
301 All authors listed made substantial contributions to the conception and design of the work, data
302 interpretation, draft and critical revision of the manuscript. All authors approved the version to be
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303 published; and agree to be accountable for all aspects of the work ensuring that question related to the
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304 accuracy of any part of the work are appropriately investigated and resolved.
305 Funding: No funding required for this project. -p

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306 References
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321 6. Urner M, Barnett AG, Bassi GL, et al. Venovenous extracorporeal membrane oxygenation in
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496 Figure caption:
497 Fig 1 PRISMA flow diagram.
498 Fig 2 Proposed clinical approach to liberation in patients with respiratory failure supported with veno-
499 venous extracorporeal membrane oxygenation and mechanical ventilation
500
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Table 1 – Liberation strategies used in ECMO studies
Author N Liberation strategy / trial Criteria for liberation Criteria for decannulation Liberation outcomes:
Combes et 124 Clinician identification of Clinical, radiological, gasometric improvement PaO2 >70 mmHg Duration of ventilation: 22 (IQR, 11-34) days
al.2 readiness for liberation compatible with improved lung compliance FiO2 <60%
Plateau pressure < 30 cmH2O
Iterative gradual reduction of No evidence of severe acute cor pulmonale
sweep gas flow to 0 L/min on echocardiography
(Duration: at least 1 hour)
Peek et al.37 68 Clinician identification of Evidence of improvement in lung compliance Adequate gas exchange Duration of ventilation: 23.9 ± 20.4 days
readiness for liberation and chest imaging Peak pressure <30 cmH2O Duration of ECMO: 9 (IQR, 6-16) days
FiO2 <60%
Iterative gradual reduction of
sweep gas flow to 0 L/min
(Duration: Not specified)
Gannon et 26 Daily standardized Off paralysis SpO2 >88% Recannulation rate: 1/14 (7.1%)
f
oo
al.21 assessment of readiness for Hemodynamic stability Respiratory rate <35 breaths/min Death after decannulation: 3/14 (21%)
liberation Sweep gas flow <3 L/min No sustained change in heart rate ≥20% Decannulation to extubation: 9 (IQR, 2-20) days
r
FiO2 <60% No sustained change systolic blood Median ventilator-free days: 11.5 (IQR, 4-14)
-p
Standardized liberation trial PEEP ≤15 cmH2O pressure to ≥180 or ≤90 mmHg Median ECMO-free days: 14 (IQR, 8-22)
(Duration: 30 minutes) SpO2 >90%, PaO2 >60 mmHg, pH >7.35 No apnea ≥3 minutes after sweep gas flow
re
Respiratory rate <35 breaths/min to 0 L/min
Teijeiro et 31 Daily standardized >12 hours of treatment of underlying disease No evidence of respiratory distress Decannulation failure: 2/19 (10%)
lP
al.44 assessment of readiness for Off paralysis >24 hours PaO2 <60 mmHg, SpO2 ≥88%, FiO2 ≤60% Recannulation: 1/19 (5%)
liberation Extracorporeal blood flow ≤5 L/min PEEP <20 cmH2O Death after decannulation: 4/19 (23%)
na
PaO2 >60 mmHg, FiO2 ≤60% pH ≥7.25, Decannulation to extubation: 11 (IQR, 2-25) days
Standardized liberation trial Sweep gas flow ≤4 L/min, pH >7.25 Tidal volume <9 ml/kg predicted body Duration of ventilation: 43 (IQR, 22-58) days
(Duration: 120 minutes) Tidal volume <9 ml/kg PBW weight Duration of ECMO: 14 (IQR, 9-28) days
ur
PEEP <20 cmH2O Hemodynamically stable
Jo
Hemodynamic stability Sedation-agitation scale 2-4
Sedation-agitation scale 2-4
No transport or procedure within 120 min Decannulation failure: Recannulation or
sustained increase in ventilatory or
hemodynamic support within 48 hours of
decannulation
Pratt et al.8 180 Daily standardized pH >7.30 SpO2 ≥88% Recannulation: 3/82 (3.7%)
assessment of readiness for PaO2 > 55 mmHg PaO2 ≥55, Death after decannulation: 10/180 (5.5%)
liberation Ventilator FiO2 ≤40% pH ≥7.30 Duration of ventilation: 15 (IQR, 9-31) days
Tidal volume ≥4 ml/kg ideal body weight respiratory rate ≤35 breaths/min Duration of ECMO: 5.5 (IQR, 3-11) days
Standardized liberation trial Hemodynamically stable
(Duration: 4 hours)
Al-Fares et 83 Clinician identification of Improvement in underlying disease and lung Clinician evaluation of risk versus benefit of Decannulation failure: 21/83 (25%)
al.9 readiness for liberation function as assessed by gas exchange, ECMO liberation Recannulation: 2/83 (2%)
respiratory system compliance and imaging Death after decannulation: 3/83 (3%)
(Duration: Variable) Decannulation failure: Recannulation or any Duration of ventilation: 23 (IQR, 15-
increase in ventilatory or hemodynamic 34)[retrospective cohort] and 16 (IQR, 9-38) days
support within 48 hours of decannulation [prospective cohort]
Duration of ECMO: 12 (IQR, 12-28)[retrospective
cohort] and 11(IQR,7-20)[prospective cohort]
days
Thiara, et al.45 87 Clinician identification of Extracorporeal blood flow <2.5 L/min Recannulation: 0/87
readiness for liberation Safe lung ventilation with low levels of Death after decannulation: 24/87 (28%)
ventilatory support Decanulation to extubation: 7 (IQR, 3-15) days
Iterative gradual reduction of Absence of increased work of breathing on Duration of ventilation: 16 (IQR, 9-28) days
sweep gas flow to 0 L/min low levels of SGF rates. Duration of ECMO: 9 (IQR,6-14) days
(Duration: 4-24 hours)
Na et al.36 93 Clinician identification of Blood gas in range with sweep ≤1 L/min pH ≥7.35 Decannulation failure:0/93
readiness for liberation Acceptable ventilator settings PaO2/FiO2 ≥150 mmHg within 30 minutes Recannulation: 0/93
Peak inspiratory pressure ≤30 cmH2O Respiratory rate <30 breaths/min Death after decannulation: 17/93 (18%)
f
oo
Iterative gradual reduction of Supplemental oxygen FiO2 ≤60% SpO2 ≥90% Duration of ventilation: 21 (IQR, 11-32) days
sweep gas flow to 0 L/min Hemodynamic stability Duration of ECMO: 10 (IQR,5-22) days
r
(Duration: 2 hours)
-p
Successful decannulation: Survival without
recannulation beyond 24 hours of
re
decannulation.
Belliato et 18 Clinician identification of Resolution of the underlying pathology Acceptable ventilatory load Recannulation: 0/15
lP
al.15 readiness for liberation Radiologic evidence of improvement Hemodynamic stability Death after decannulation: 1/15 (7%)
Improving respiratory mechanics Adequacy of gas exchange Duration of ECMO: 11 (IQR,7-15) days
na
Iterative gradual reduction of PEEP <10-15 cmH2O
sweep gas flow to 0 L/min Hemodynamic stability
(Duration: 6-12 hours)
ur
Fisser et al.20 227 Clinician identification of Resolution of underlying disease Absence of subjective dyspnea
Jo
readiness for liberation Hemodynamic stability Respiratory rate >35 breaths/min
SpO2 ≥90% on FiO2 ≤0.4 SpO2 ≤90%
Iterative gradual reduction of PEEP ≤10 cmH2O Heart rate >120 beats/min
sweep gas flow to 0 L/min Respiratory rate ≤30 breaths/min Absence of blood gas deterioration
(Duration: ≥30 minutes) Tidal volume >5 ml/kg
Extracorporeal blood flow ~1.5 L/min
Hartley et al.24 253 Clinician identification of Tidal volume improvement to >2-3 ml/kg PBW Duration of ECMO: 9 (IQR, 6-14) days
readiness for liberation

(Duration: Not specified)
Gurnani et 62 Clinician identification of Improved aeration on chest X-ray Patients must tolerate being of sweep gas Death after decannulation: 9/62 (14%)
al.23 readiness for liberation Appropriate blood gas parameters flow and ambulate CANNULATION to extubation: 6 (IQR, 4-11) days
Normal saturation Duration of ECMO: 33 (IQR, 20-75) days
Iterative gradual reduction of Activity tolerance
sweep gas flow to 0 L/min Supplemental oxygen <6 L/min rest or <15
(Duration: 24 hours) L/min during exertion
Masi et al.33 51 Clinician identification of Ventilator FiO2 ≤60% Conventional weaning Decannulation failure*:13/18 [facilitated weaning]
readiness for liberation Tidal volume ≥6 mL/kg PBW PaO2 ≥60 mmHg 2/16 [conventional weaning]
Respiratory rate ≤28 breaths/min PaCO2 ≤50 mmHg or pH ≥7.36 Recannulation: 0/34
Iterative gradual reduction of Plateau pressure ≤28 cmH2O FiO2 ≤60% Death after decannulation: 3/34 (11%) [2
sweep gas flow to 0 L/min Protective mechanical ventilation facilitated weaning, 1 conventional weaning]
(Duration: Not specified) Decannulation to extubation: 5 (IQR, 4-11) days
Facilitated weaning [conventional weaning], 26 (IQR, 13-36) days
Recovered native lung oxygenation [facilitated weaning]
Failed liberation trial Duration of ventilation: 21 (IQR, 14-31) days
Liberated without meeting liberation criteria [conventional weaning], 55 (IQR, 16-36) days
[facilitated weaning]
Duration of non-protective ventilation (plateau
pressure ≥30 cmH2O, driving pressure >15
cmH2O): 1 (IQR, 0-2) days [conventional
f
oo
weaning], 6 (IQR, 4-10) days [facilitated weaning]
Duration of ECMO: 10 (IQR, 7-14) days
[conventional weaning], 24 (IQR, 16-43) days
r
-p
[facilitated weaning]
Lazzari et 664 Daily standardized Prospective cohort Prospective cohort Duration of ECMO: 10 (IQR, 6-18) days
re
al.27 assessment of readiness for Assisted ventilation with pressure support Esophageal pressure swings ≤15 cmH2O
liberation Esophageal pressure swings ≤15 cmH2O Respiratory rate ≤30 cmH2O
lP
Respiratory rate ≤30 cmH2O PaO2 ≥70 mmHg, FiO2 ≤60%
Standardized liberation trial PaO2 ≥70 mmHg, FiO2 ≤60% PaCO2 ≤60 mmHg, pH >7.25
na
(Duration: Not specified) PaCO2 ≤60 mmHg, pH >7.25
Retrospective cohort
Retrospective cohort SpO2 ≥88% on FiO2 60%
ur
Resolution of underlying disease P0.1 ≤10 cmH2O
Spontaneous breathing on pressure support Respiratory rate ≤35 breaths/min
Jo
Hemodynamic stability No obvious signs of distress

pH ≥7.35
Reeb et al.39 8 Clinician identification of Pulmonary compliance improved Satisfactory blood gases after 4 hours on Recannulation:0/8
readiness for liberation FiO2 <50% sweep gas flow 0 L/min Death after decannulation:3/8 (25%)
PEEP <5 cmH2O Duration of ventilation: 17 (IQR, 10-19) days
Iterative gradual reduction of Plateau pressure <30 cmH2O Duration of ECMO: 9.5 (IQR, 5-16) days
sweep gas flow to 0 L/min Tidal volume >4 mL/kg predicted body weight
(Duration: 4 hours)
Seiler et al.40 12 Clinician identification of PaO2, PaCO2 and pH within physiologic range Satisfactory gases at sweep gas flow 0 Recannulation:4/7 (not within 28 days)
readiness for liberation L/min Death after decannulation:1/7 (14%)
Duration of ventilation: 17 (IQR, 10-19) days
Iterative gradual reduction of Duration of ECMO: 32±14 days (recovery),
sweep gas flow to 0 L/min 98±50 days (transplanted)
(Duration: minimum 1 hour)
* Not defined in the publication. Proportions based on the definition proposed by Al-Fares [9]: Recannulation or any increase in ventilatory or hemodynamic support within 48 hours of decannulation.
Table 2 – Examples of standardized liberation strategies reported in literature
Author Protocolized liberation strategy - steps Criteria for liberation/Remarks
Shekar et al.42 1. Daily blood flow down-titration challenge (300 mL/min decrements) to identify lowest • Proposed advantages: Dynamic adjustments in extracorporeal blood flow
tolerable blood flow while maintaining ultraprotective ventilation and SpO2 ≥88% on FdO2 allow more aggressive fluid restriction, expediting lung recovery.
100%, FiO2 50% • Potential disadvantages: Requires optimized anticoagulation.
2. Oxygenation challenge (FiO2 100%) – target PaO2 >250 mmHg on PEEP ≤10 cmH2O
3. Iterative gradual reduction in FdO2 & sweep gas flow targeting plateau pressure ≤24
cmH2O, PEEP ≥10 cmH2O, or simply set sweep gas flow to 0 L/min
Kimmoun et 1. Daily optimization of ECMO blood flow based on cardiac output measured by • Liberation was considered if targets for step 4 were met after 12-24
al.26 echocardiogram, targeting blood flow/cardiac output ratio of at least 0.7. hours on sweep gas flow 0 L/min.
2. Titrate sweep gas flow to PaCO2 40-45 mmHg • Patients were proned on ECMO when there was a failure to wean
3. After 48 hours of treatment, increase tidal volume daily, targeting plateau ≤25 cmH2O support after 7 days or during refractory hypoxemia (PaO2/FiO2 <150
4. When tidal volume >5 mL/Kg predicted body weight and respiratory rate >15 breaths/min, mmHg on FdO2 100%, FiO2 50%) or PPlat >25 cmH2O
progressively reduce sweep gas flow to 0 mL/min, targeting PaO2/FiO2 >150 mmHg, FiO2
<60%, PaCO2 <50 mmHg, plateau pressure ≤25 cmH2O
f
oo
Broman et al.16 Karolinska approach
1. Weaning starts as soon as tidal volumes start to recover.
r
2. Sweep gas flow is adjusted to daily preset goals for pH and PaCO2
-p
3. When sweep gas is ≤2 L/min, incremental CO2 is added to the gas mixture, targeting a
maximum FdCO2 corresponding to 37.5 mmHg
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4. When the pre-post membrane PCO2 difference is < 1.5-3 mmHg, turn sweep gas flow to
0 L/min, on FiO2 35-55%
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Grant et al.22 1. Normocapnia and SpO2 >90% on FiO2 <50%, PEEP ≤10 cmH2O, tidal volume 6-8 mL/Kg • Normocapnia and SpO2 >90%, on protective ventilatory settings, blood
ideal body weight, peak inspiratory pressure <30 cmH2O and plateau pressure ≤25 flow <3-4 L/min and sweep gas flow <1 L/min
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cmH2O, respiratory rate to target 100 mL/kg minute ventilation, on blood flow 4-5 L/min,
sweep gas flow 3-4 L/min, FdO2 100%
2. Wean FdO2 to 21%, target SpO2 >90%
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3. Wean blood blood flow to 3-4 L/min for 24-48 hours
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4. Wean sweep gas flow to <1 L/min in the following 24-48 hours targeting normocapnia
Vasques et al.47 1. Prerequisites for a liberation assessment: breathing comfortably, off paralytics, • Failure criteria: SpO2 <88%, respiratory rate >35 breaths/min, P0.1 >10
hemodynamic stability, P0.1 <5 cmH2O mmHg, esophageal pressure swings >15 cmH2O, respiratory distress,
2. Oxygen challenge test: FiO2 100%, target PaO2 >225 mmHg hemodynamic instability.
3. ECMO Deoxygenation challenge: reduce FiO2 to 60%, followed by stepwise (every 5
minutes) reduction of FdO2 to 21% (100-60-30-21), monitor for failure criteria
4. ECMO CO2 challenge: Stepwise (every 5-10 minutes) 33% reduction in sweep gas flow
to 0 L/min, while keeping blood flow fixed, monitor for failure criteria
Combes et al.19 1. Recovery of native lung function (FiO2 <60%, sweep gas <8 L/min, tidal volume ≥4.5 After 1-12 hours off sweep gas
mL/kg predicted body weight, plateau ≤25 cmH2O, driving pressure ≤14 cmH2O) • PaO2 ≥60 mmHg, SaO2 ≥90% on FiO2 ≤60%
2. Set ventilator to tidal volume 6 ml/Kg predicted body weight, respiratory rate ≤28 • PaCO2 ≤50 mmHg or pH ≥7.36 with respiratory rate ≤28 breaths/min
breaths/min, PEEP 6-14 cmH2O, FiO2 ≤60% - target plateau pressure ≤28 cmH2O • Plateau pressure ≤28 cmH2O
3. Turn sweep gas flow to off, target SpO2 ≥90% on FiO2 ≤60% • No signs of acute cor pulmonale
Tonna et al.46 1. Sufficient conditions to initiate a weaning trial (FiO2 ≤60%, PEEP ≤10 cmH2O, PaO2 ≥70 • If patient able to tolerate discontinuation of ECMO for 2-3 hours or
mmHg, tidal volume ≤6 ml/Kg predicted body weight, respiratory rate ≤28 breaths/min, longer.
plateau pressure ≤28 cmH2O, arterial blood gases with acceptable pH for patients
condition without excessive work of breathing, improving imaging.
2. Perform a ventilator challenge: liberalize tidal volume by 1 ml/Kg increments up to 6
ml/Kg predicted body weight, target plateau pressure ≤28 cmH2O
3. Stepwise reduction in FdO2 from 100 to 21% in 20% decrements, or blood flow reduction
to 1-1.5 L/min, target SpO2 >92%, or PaO2 ≥70 mmHg.
4. Stepwise reduction in sweep gas flow by 0.5-1 L/min decrements to 1 L/min
5. Maintain acceptable pH based on clinical condition without excessive work of breathing.
Gannon et al.21 1. Perform an ECMO-free trial safety screen – sweep gas flow ≤3 L/min • Pragmatic liberation trials emulating spontaneous breathing trials.
2. Non-ECMO FiO2 titration – set FiO2 to 60% Trial termination criteria:
3. ECMO-Free trial – Turn FdO2 to 50% for 5 minutes, then turn sweep gas to 0 L/min. • SpO2 ≤88%
• Respiratory rate ≥35 breaths per minute
• Sustained increase or decrease in heartrate of ≥20%
• Systolic blood pressure ≥180 mmHg or ≤90 mmHg
• No spontaneous breathing after 3 minutes off sweep
Teijeiro et al.44 1. Perform screening criteria for standardized liberation trial eligibility • Pragmatic liberation trials emulating spontaneous breathing trials.
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2. Optimize sedation and mechanical ventilation Trial termination criteria
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3. Turn sweep gas to 0 L/min • Increased work of breathing:
o Increase in tidal volume to >9ml/kg predicted body weight
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o Patient expressed significant shortness of breath and evidence
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of respiratory distress with diaphoresis and/or use of accessory
muscles/nasal flaring and hemodynamic changes.
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• Hypoxemia
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o SpO2 <88% for greater than 5 minutes
o FiO2 >60% to keep SpO2 > 88%
o PaO2 <60 mmHg on FiO2 of 60% in the 15 min blood gas.
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o PEEP required to keep SpO2>88% >20 cmH2O.
• Respiratory acidosis:
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o pH <7.25 +/- PCO2 >60 mmHg on the 15 min blood gas.
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• Hemodynamic instability:
o Mean arterial pressure <65 mmHg >5 minutes without
vasopressor support.
o Sustained systolic blood pressure >180 mmHg for >5 minutes
• Neurological changes
Lazzari et al.27 1. Weaning criteria: Assisted ventilation with pressure support, tidal swing of esophageal • Standardized stepwise reduction liberation trials.
pressure ≤15 cmH2O, respiratory rate ≤30 breaths/min, pH >7.25, PaCO2 ≤60 mmHg, • Termination criteria: If weaning criteria were not met at each reduction of
PaO2 ≥70 mmHg, FiO2 ≤60%. sweep gas flow.
2. Three step reduction of sweep gas flow from the original value by 33% every 20 minutes.
3. Measure weaning criteria at the end of each 20-minute interval.
Table 3 – Respiratory parameters during liberation trials
Reference Gannon 21 Teijeiro 44 Al-Fares 9 Fisser 20 Hartley 24 Masi* 33 Lazzari ⴕ 27
N 26 31 83 221 253 51 26 638
Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR)
Pre-liberation trial: Successful trials (trial led to decannulation)
SGF, L/min 2(2-3) 3(2-4) 1(0.5-1) 1.6(0.3-3) 0.5(0.5-1)
SpO2, % 98(95-100)
PPlat, cmH2O 24.5(20-28) 26(24-29)
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PEEP, cmH2O 10(10-12) 10(10-14) 12(11-14) 10(5-10)
VT, ml/kg PBW 4.1(3.5-6.0) 6(5-8) 5.71(5.24-7.2) 7.9(6.2-9.9)
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RR, bpm 21(20-25) 26(26-36) 16(11-20) 19(15-24)
FiO2 0.5(0.5-0.5) 0.5(0.4-0.5) 0.4(0.35-0.45) 0.30(0.3-0.4)
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PaO2, mmHg 92(70-131) 85(71-105) 91(80-114)
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PaCO2, mmHg 44(41-49) 42(41-46) 45(41-49)
pH 7.42(7.39-7.46) 7.38(7.36-7.41) 7.40(7.38-7.43)
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POcc, cmH2O -19(-27,-11) -6(3-7) ǀ
P0.1, cmH2O -5(-6,-3)

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Post-liberation trial: Successful trials (trial led to decannulation)
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SpO2, % 96(92-98) 97(95-97)

PPlat, cmH2O 29(24-32) 25(22-29) 25(22-26)
PEEP, cmH2O 10(10-14) 10(10-10) 10(8-21) 10(7-12)
VT, ml/kg PBW 7(6-9) 7.1(6.0-9.2) 540(430,690) ǁ
5.8(5.5-6.1)
RR, bpm 23(21-26) 27(22-35) 22(18-28) 15(13-22)
FiO2 0.5(0.4-0.6) 0.5(0.4-0.5) 0.35(0.3-0.4) 0.5(0.4-0.5)
PaO2, mmHg 97(70-129) 84(76-104)
PaCO2, mmHg 48(42-54) 41(35-45) 41(38-47) 41(37-44)
pH 7.41(7.36-7.45) 7.42(7.36-7.44)
POcc,/PESǀ cmH2O -25(-28,-15) -9(7-13) ǀ
P0.1, cmH2O -3(-5,-3) -3.1(-4,-2.5)
Pre-liberation trial: Failed trials (sweep gas flow restarted)
SGF, L/min 2(2-3) 3(2-4) 1(0.5-1) 2.5(1.2-4.7) 1(0.5-1.5)
SpO2, % 95(94-97)
PPlat, cmH2O 26(24-27) 29(25-34)
PEEP, cmH2O 10(10-12) 10(10-12) 13(12-14) 10(5-10)
VT, ml/kg PBW 4.4(3.3-6.1) 6(5-7) 5.02(3.8-6) 7.72(6-9.5)
RR, bpm 24(17-26) 26(19-30) 14(10-21) 21(16-27)
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FiO2 0.5(0.4-0.6) 0.4(0.4-0.5) 0.4(0.4-0.5) 0.3(0.3-0.4)
PaO2, mmHg 81(79-99) 78(75-89) 84(73-105)
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PaCO2, mmHg 43(42-53) 43(40-47) 46(42-51)
pH 7.43(7.38-7.46) 7.38(7.36-7.42) 7.39(7.36-7.42)
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POcc, cmH2O -29(-37,-17) -7(3-8) ǀ
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P0.1, cmH2O -6(-8,-4)
Post-liberation trial: Failed trials (sweep gas flow restarted)
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PPlat, cmH2O 34(31-38) 32(31-33) 31(29-34)
PEEP, cmH2O 10(10-12) 8(7-15) 5(5-8)
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VT, ml/kg PBW 7(6-8.5) 8.2(8.1-9) 5.6(4.8-5.9)
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RR, bpm 30(24-35) 30(27-35) 35(36-39) 19(15-25)

FiO2 60(50-65) 40(30-40) 50(40-60)
PaO2, mmHg 82(71-96)
PaCO2, mmHg 40(35-43) 43.9(39-48) 47(42-55)
pH 7.35(7.27-7.38)
POcc, cmH2O -33(-44,-28) -18(-25,-7) ǀ
P0.1, cmH2O -8(-11,-6) -4.7(-5.3,-4.1)

PPlat: plateau pressure, VT: tidal volume in ml/kg predicted body weight, RR: respiratory rate in breaths per minute, POcc: pressure of the airway during an expiratory
occlusion, P0.1: pressure of the airway during the first 100 msec of the inspiratory effort, PES: esophageal pressure during inspiratory tidal swings in cmH2O .
*Trials were divided in facilitated weaning and conventional weaning. Failed trials correspond to data from the facilitated weaning group.
ⴕ Study included a prospective cohort (n=26) and a retrospective cohort (n=638)
ǀ
Esophageal pressure during inspiratory tidal swings in cmH2O
ǁ
Tidal volume in ml
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Table 4 – Predictors of liberation outcomes used in clinical studies
Author N Predictors reported in studies related to liberation Estimates
Al-Fares et al.9 Outcome - safe liberation
28 Tidal volume within 4 hours of sweep gas flow 0 L/min OR 2.1 (95% CI, 1-4.4; p 0.05) [1 ml/kg predicted body weight]
(unadjusted) Optimal cutoff: 7.8 ml/kg predicted body weight
Sensitivity: 100%
Specificity: 71.4%
AUC: 0.813
Heart rate within 4 hours of sweep gas flow 0 L/min OR 1.09 (95% CI, 1.0-1.1; p 0.02)
(unadjusted) Optimal cutoff: 110 beats/min
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Sensitivity: 71.4%
Specificity: 85.7%
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AUC 0.82
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Ventilatory ratio within 4 hours of sweep gas flow 0 L/min OR 5.07 (95% CI, 1.2-21.3; p 0.03)
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(unadjusted) Optimal cutoff: 2.3
Sensitivity: 71.4%
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Specificity: 85.7%
AUC: 0.82
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Esophageal pressure swing within 4 hours of sweep gas flow 0 L/min OR 1.28 (95% CI, 1-1.5; p 0.02)
(unadjusted) Optimal cutoff: 16
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Sensitivity: 71.4%
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Specificity: 100%
AUC: 0.77
55 Tidal volume one hour prior to decannulation OR 1.58 (95% CI, 1.05-2.40; P= .03)
(adjusted for age and SOFA)
Heart rate one hour prior to decannulation OR 1.08 (95% CI, 1.02-1.15: P= .01)
Ventilatory ratio one hour prior to decannulation OR 2.7 (95% CI, 0.94-7.95; P = .06)
Lazzari et al.27 Outcome – weaning success
26 PetCO2/PaCO2 prior to sweep gas flow 0 L/min Optimal cutoff: ≥0.84
Sensitivity: 91.7%
Specificity: 80%
AUC 0.87 (95% CI 0.71-1)
Positive likelihood ratio 4.6
Correctly classified patients: 86%
638 PetCO2/PaCO2 prior to sweep gas flow 0 L/min OR 4.1 (95%CI 1.3-12.2; p=0.015)
(unadjusted) Optimal cutoff: ≥0.83
Sensitivity: 54%
Specificity: 66%
AUC 0.58 (95% CI 0.53-0.63)
Positive likelihood ratio 1.6
PetCO2/PaCO2 at sweep gas flow 0 L/min OR 13.1 (95% CI, 4-44: p<0.001)
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(unadjusted)
PaO2/FiO2 at sweep gas flow 0 L/min OR 1.06 (95% CI, 1.04-1.07: p<0.001)
r
(unadjusted)
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Hartley et al.24 Outcome - decannulation
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253 PaO2 oxygen challenge test within 48 hours prior to decannulation Optimal cutoff: 232 mmHg
(Cilley test) Sensitivity: 74%
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Specificity: 70%
AUC 0.77 (95% CI 0.73-0.81)
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ECMO minute volume within 12 hours of first positive oxygen 4.82 ± 3.43 vs 1.66 ± 2.26 L/min
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challenge test AUC 0.88 (95% CI 0.88-0.89)
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Composite criteria including ECMO minute volume Oxygen challenge test:
AUC 0.89 (95% CI, 0.88-0.89)
OR 1.006 (95% CI, 1.004-1.009)
Expiratory minute volume:
AUC 0.89 (95% CI, 0.88-0.89)
OR 1.02 (95% CI, 1.01-1.03)
Corrected expiratory minute volume:
AUC 0.90 (95% CI, 0.89-0.90)
OR 0.99 (95% CI, 0.99-1)
SOFA; sequential organ failure assessment scale, AUC; area under the receivers operation characteristics curve, OR; odds ratio
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐ The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
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Supplementary material - Review protocol
Liberation form veno-venous extracorporeal membrane oxygenation for respiratory failure: a

scoping review
1. Rationale:
Veno-venous extracorporeal membrane oxygenation (V-V ECMO) reduces mortality in patients

with severe acute respiratory distress syndrome (ARDS).1-6 Due its complexity, patient selection
has been extensively refined.7 However how efficiently liberate patients from V-V ECMO remains
understudied. Timely liberation would be expected to reduce duration of ECMO, the risk of ECMO-
related complications, and costs.8 Conversely, premature liberation can induce lung injury.9 This
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trade-off between longer ECMO runs to mitigate lung injury versus the exposure to ECMO-related
complications as patients improve has not been well defined.
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To our knowledge, no prior scoping reviews on the topic using systematic search strategies have
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been published. A systematic review is registered in PROSPERO and appears to be in development,
however has not been published yet (Karina Chahinian, Francis Charbonneau, Olivier Lavigueur,
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Emmanuel Bebawi, Yiorgos Alexandros Cavayas. Parameters Associated with Weaning Success in
Patients with Acute Respiratory Failure on VV-ECMO: A Systematic Review. PROSPERO 2021
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CRD42021236127 Available from:

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021236127). Contrary to this
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systematic review outlining parameters associated with weaning success, our scoping review aims
to provide an outline of the strategies and methods used to liberate patients from V-V ECMO to
date.
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2. Objective:
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The objective of this scoping review is to outline current definitions, protocols and strategies used
to liberate patients from V-V ECMO, and to identify gaps in knowledge on liberation.
3. Inclusion criteria:
Publications will be included if they report criteria to start liberation from V-V ECMO, a liberation
protocol, and a definition of successful decannulation or decannulation failure. We will include
randomized controlled trials, observational trials, narrative reviews, guidelines, editorials,
commentaries, and excluded single case reports and citations with unavailable full text.
4. Information sources and search strategy:
Ovid MEDLINE: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE®
Daily and Ovid MEDLINE® <1946-May 2022>
1-. ((ECMO or extracorporeal membrane oxygenation) adj2 liberation).tw,kf.

2-. ((ECMO or extracorporeal membrane oxygenation) adj2 weaning).tw,kf.
3-. ((ECMO or extracorporeal membrane oxygenation) adj2 separation).tw,kf.
4-. ((ECMO or extracorporeal membrane oxygenation) adj10 (protocol and (weaning or liberation
or separation or strategy or test))).tw,kf.
5-. extracorporeal membrane oxygenation.mp. and liberat*.tw,kf. [mp=title, abstract, original title,
name of substance word, subject heading word, floating sub-heading word, keyword heading
word, organism supplementary concept word, protocol supplementary concept word, rare disease
supplementary concept word, unique identifier, synonyms]
6-. 1 or 2 or 3 or 4 or 5
Embase Classic+Embase <1947 to 2022 May 06>
1-. ((ECMO or extracorporeal membrane oxygenation) adj2 liberation).tw,kf.

2-. ((ECMO or extracorporeal membrane oxygenation) adj2 weaning).tw,kf.
3-. ((ECMO or extracorporeal membrane oxygenation) adj2 separation).tw,kf.
4-. ((ECMO or extracorporeal membrane oxygenation) adj10 (protocol and (weaning or liberation
of
or separation or strategy or test))).tw,kf.
5-. extracorporeal membrane oxygenation.mp. and liberat*.tw,kf. [mp=title, abstract, heading
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word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name,
keyword heading word, floating subheading word, candidate term word]
6-. 1 or 2 or 3 or 4 or 5
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Set of key publications selected a priori to maximize sensitivity and specificity of the systematic
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search:
• Al-Fares AA, Ferguson ND, Ma J, Cypel M, Keshavjee S, Fan E, Del Sorbo L, (2021) Achieving
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Safe Liberation During Weaning From VV-ECMO in Patients With Severe ARDS: The Role of
Tidal Volume and Inspiratory Effort. Chest 160: 1704-1713
• Gannon WD, Stokes JW, Bloom S, Sherrill W, Bacchetta M, Rice TW, Semler MW, Casey JD,
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(2021) Safety and Feasibility of a Protocolized Daily Assessment of Readiness for Liberation
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From Venovenous Extracorporeal Membrane Oxygenation. Chest 160: 1693-1703

• Teijeiro-Paradis R, Tiwari P, Spriel A, Del Sorbo L, Fan E, (2021) Standardized liberation
trials in patients with COVID-19 ARDS treated with venovenous extracorporeal membrane
oxygenation: when ready, let them breathe! Intensive Care Med 47: 1494-1496
• Pratt EH, Mausert S, Wilson MD, Emerson LJ, Navuluri N, Pulsipher AM, Brucker A, Green
CL, Bonadonna DK, Bryner BS, Rackley CR, (2021) A Daily, Respiratory Therapist
Assessment of Readiness to Liberate From Venovenous Extracorporeal Membrane
Oxygenation in Patients With Acute Respiratory Distress Syndrome. Crit Care Explor 3:
e0584
• Thiara S, Serpa Neto A, Burrell AJC, Fulcher BJ, Hodgson CL, (2022) Association of
Respiratory Parameters at Venovenous Extracorporeal Membrane Oxygenation Liberation
With Duration of Mechanical Ventilation and ICU Length of Stay: A Prospective Cohort
Study. Crit Care Explor 4: e0689
5. Data synthesis and data extraction:
EndNote X9.2 (Clarivate Analytics) will be used to remove duplicates. Two reviewers (RTP, TCD)
will independently screen publications for retrieval and eligibility. For any disagreement on
inclusion of publications, the full text and supplementary material will be carefully reviewed again,
and a third reviewer (EF) will make a final decision if disagreement persists.
First screen (data retrieval) - Title + Abstract – (RTP, TCD):
- Include all V-V ECMO studies that made reference to liberation/weaning

- Exclude all V-A ECMO studies, animal or experimental models, duplicates, Non-ECMO
studies
Second screen (data eligibility) - Abstract + Full text + Supplementary material – (RTP, TCD):
- Include all papers that include:

o A definition of successful decannulation or failure; and/or
o Criteria to start liberation; and/or
o A liberation strategy or protocol
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- Exclude papers without any of the above, single case reports and papers without full text
available.
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Data will be extracted by two reviewers (RTP, TCD) after completion of the retrieval and eligibility
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scanning process. Data items of interest include:
- Criteria used to identify lung recovery

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- Criteria to identify readiness for liberation testing
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- Strategies or protocols used to liberate patients from V-V ECMO for respiratory failure
- Description of the liberation trial used
- Parameters monitored during a liberation trial
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- Parameters used to predict decannulation outcome

- Parameters used to proceed with decannulation
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- Definitions of successful or failed decannulation
As the main objective of this scoping review is to give an overview of the available evidence, no
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risk of bias will be performed, no effect measures or synthesis methods will be employed, and no
meta-regression or methods to explore statistical heterogeneity will be used.
6. Results and discussion:
Study selection results will be presented using a PRISMA flow diagram. Included publications will
be cited, and key characteristics will be described in tables. Information from included publications
will then be stratified, summarized, and discussed in the following subtopics:
- Current strategies used for liberation from V-V ECMO

- Criteria used to define readiness for liberation
- Performing ECMO liberation trials
- Criteria used to proceed with decannulation
- Parameters used to predict decannulation outcomes
7. Other information:
As this is a scoping review, the systematic search strategy will not be registered in PROSPERO. The
review protocol will be registered in OSF (Open Science Framework).
References
1 Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation

support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization
registry. Lancet 2020; 396: 1071-8.
2 Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe
Acute Respiratory Distress Syndrome. The New England journal of medicine 2018; 378: 1965-75.
3 Combes A, Peek GJ, Hajage D, et al. ECMO for severe ARDS: systematic review and
of
individual patient data meta-analysis. Intensive care medicine 2020; 46: 2048-57.
ro
4 Goligher EC, Tomlinson G, Hajage D, et al. Extracorporeal Membrane Oxygenation for
Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a
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Post Hoc Bayesian Analysis of a Randomized Clinical Trial. JAMA : the journal of the American
Medical Association 2018; 320: 2251-9.
5 Munshi L, Walkey A, Goligher E, Pham T, Uleryk EM, Fan E. Venovenous extracorporeal
re
membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-
analysis. Lancet Respir Med 2019; 7: 163-72.
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6 Urner M, Barnett AG, Bassi GL, et al. Venovenous extracorporeal membrane oxygenation
in patients with acute covid-19 associated respiratory failure: comparative effectiveness study.
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Bmj 2022; 377: e068723.

7 Bullen EC, Teijeiro-Paradis R, Fan E. How I Select Which Patients With ARDS Should Be
Treated With Venovenous Extracorporeal Membrane Oxygenation. CHEST 2020; 158: 1036-45.
ur
8 Pratt EH, Mausert S, Wilson MD, et al. A Daily, Respiratory Therapist Assessment of
Readiness to Liberate From Venovenous Extracorporeal Membrane Oxygenation in Patients With
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Acute Respiratory Distress Syndrome. Crit Care Explor 2021; 3: e0584.

9 Al-Fares AA, Ferguson ND, Ma J, et al. Achieving Safe Liberation During Weaning From VV-
ECMO in Patients With Severe ARDS: The Role of Tidal Volume and Inspiratory Effort. Chest 2021;
160: 1704-13.

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Liberation form veno-venous extracorporeal membrane oxygenation for respiratory

Ricardo Teijeiro-Paradis, Tsega Cherkos-Dawit, Laveena Munshi, Niall D. Ferguson,

To appear in: CHEST

Received Date: 4 March 2023

Liberation form veno-venous extracorporeal membrane oxygenation for respiratory failure: a

Short title: Liberation from V-V ECMO a scoping review.

Ricardo Teijeiro-Paradis1, Tsega Cherkos-Dawit1, Laveena Munshi1,2,3,4, Niall D. Ferguson1,2,3,4,5,

Toronto General Hospital

585 University Avenue, 9-MaRS-9013

Conflicts of interest, competing interest, and sources of funding:

15 and parameters used to predict decannulation outcomes.

19 Keywords: ECMO, respiratory failure, weaning, liberation

38 Framework (OSF - https://doi.org/10.17605/OSF.IO/UH9ND). Two reviewers (RTP, TCD) independently

49 decannulation outcomes (success/failure, unsafe liberation) (Table 4). Finally, we constructed an

51 important gaps in knowledge (Figures 2 & 3).10

60 (emulating spontaneous breathing trials).

63 (Figure 1).2,8,9,14-49 We included 2 cross-sectional surveys describing heterogeneity in liberation

64 practices,32,43 13 reviews describing multiple aspects of liberation,16-19,22,30,36,40-42,46,47,49 2 publications

65 defining decannulation outcomes,28,48 4 citations suggesting criteria of readiness to liberate,25,29,31,38 and

66 18 publications reporting the strategy used to liberate patients from ECMO.2,8,9,14,15,20,21,23,24,26,33-

72 clinician guided iterative reduction of ECMO support.2,9,15,20,23,24,33,35,37,39,40,45 A total of nine publications

79 decannulation success/failure.9,28,29,48 Seven observational studies included patients with Coronavirus

86 superimposed ventilator associated pneumonia), or multiple failed liberation attempts – where

118 evidence based cutoff values to guide decision-making.

130 liberation trial.46

137 Criteria to define readiness for liberation

149 recommendation: expert opinion). 21,44

156 Performing ECMO liberation trials

165 support, and standardized liberation trials.

183 decannulation remains undefined.9,35

204 Criteria to proceed with decannulation

221 clinician preferences.

232 Parameters to predict decannulation outcomes

240 second round of ECMO in patients with complicated clinical trajectories.

247 their utility to identify mechanisms of liberation failure need to be highlighted.

257 Future directions:

270 systematically approach liberation failure.

279 not be generalizable to current or future conditions.

291 Take Home Point:

298 liberation topics.

300 Statement of authorship:

305 Funding: No funding required for this project. -p

328 Respiratory Distress Syndrome. Crit Care Explor. 2021;3(12):e0584.

333 medicine. 2012;367(23):2233-2239.

374 patients undergoing extracorporeal membrane oxygenation (ECMO). J Card Surg.

377 failure: weaning versus nonweaning. Asaio j. 2015;61(2):184-189.

425 corporeal membrane oxygenation. Crit Care. 2019;23(1):316.

430 Care Unit Issues. Crit Care Clin. 2017;33(4):843-853.

470 membrane oxygenation. Intensive Care Medicine. 2022;48(8):1076-1079.

473 Thorac Soc. 2016;13(12):2242-2250.

497 Fig 1 PRISMA flow diagram.

Iterative gradual reduction of

Hemodynamic stability No obvious signs of distress

P0.1, cmH2O -5(-6,-3)

SpO2, % 96(92-98) 97(95-97)

RR, bpm 30(24-35) 30(27-35) 35(36-39) 19(15-25)

P0.1, cmH2O -8(-11,-6) -4.7(-5.3,-4.1)

Liberation form veno-venous extracorporeal membrane oxygenation for respiratory failure: a

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) reduces mortality in patients

CRD42021236127 Available from:

4. Information sources and search strategy:

1-. ((ECMO or extracorporeal membrane oxygenation) adj2 liberation).tw,kf.