The ECMO-Free Trial

Study Overview
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Brief Summary
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Decannulation from venovenous extracorporeal membrane oxygenation (VV-ECMO) at the earliest and safest time would be expected to improve outcomes and reduce cost. Daily assessments for readiness to liberate from therapies have demonstrated success in other realms of critical care. A recent single-center study demonstrated that a protocolized daily assessment of readiness for liberation from VV-ECMO was feasible and did not raise any major safety concerns, but the effect of this protocolized daily assessment on clinical outcomes remains unclear. Further, the manner in which ECMO is provided, weaned, and discontinued varies significantly between centers, raising persistent concerns regarding widespread adoption of protocolized daily assessment of readiness for liberation from VV-ECMO. Data from large a randomized controlled trial is needed to compare the effects of a protocolized daily assessment of readiness for liberation from VV-ECMO versus usual care on duration of ECMO support and other clinical outcomes. Before such a trial can be conducted, however, additional data are needed to inform the feasibility of a multi-center trial of ECMO weaning.

Detailed Description
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Complication rates, economic consequences, and resource limitations associated with the use of venovenous ECMO (VV-ECMO) are widely recognized. Decannulation at the earliest and safest possible time would be expected to improve clinical outcomes, reduce cost, and optimize resource allocation. Yet, there are no data comparing weaning strategies for decannulation from VV-ECMO, and there is significant variation between centers in approaches to weaning VV-ECMO. Current approaches to weaning VV-ECMO generally rely on clinicians to identify signs of lung recovery and initiate incremental reductions in blood flow rate, fraction of delivered oxygen (FdO2), and sweep gas flow rate4-6. This approach has been previously outlined in guidelines distributed by the Extracorporeal Life Support Organization, expert opinion, and in small descriptive studies, though little data exist to support this strategy. Further, these approaches run counter to the large body of literature for assessing readiness for liberation from sedation and mechanical ventilation in which incremental reductions (weaning) have repeatedly been shown to be inferior to protocolized daily assessments (spontaneous awakening trials and spontaneous breathing trials7-11). Prior data suggest that clinicians underestimate readiness for liberation from organ support and suggest that protocols to identify readiness for liberation are superior to clinician judgement9,11. Compared to incremental weaning, spontaneous awakening trials and spontaneous breathing trials have been shown to dramatically shorten the duration of support, reduce intensive care costs, and improve outcomes7-13. Until recently, this approach to liberating patients from a therapy had not been applied to ECMO. Our groups recently conducted a 26-patient, prospective, single-arm, safety and feasibility study to develop and refine a protocol for daily assessment of readiness to liberate from VV-ECMO at a single center14. The results of this study, published in CHEST, suggested that a protocolized daily assessment of readiness for liberation from VV-ECMO is feasible and safe. Further, the median time from first passed trial to decannulation was 2 days, suggesting that a daily protocolized assessment might identify candidates for decannulation earlier than occurs in usual care. However, as a single-arm feasibility study, the prior study was insufficient to determine whether dedicating resources to a protocolized daily assessment of readiness to liberate from VV-ECMO affects patient outcomes. Further, the manner in which ECMO is provided, weaned, and discontinued varies significantly between centers, raising persistent concerns regarding the feasibility of widespread adoption of protocolized daily assessment of readiness for liberation from VV-ECMO. A large, randomized trial is needed to determine whether a protocolized daily assessment of readiness to liberate from VV-ECMO affects patient outcomes. Before such a trial can be conducted, however, additional data are needed to establish the feasibility of randomizing patients to a specific weaning strategy across multiple centers. Additional data from a large, multi-center randomized controlled trial are needed to compare the effects of a protocolized daily assessment of readiness for liberation from VV-ECMO versus usual care on duration of ECMO support, measures of unsafe liberation, and other clinical outcomes. Primary aim: Demonstrate the feasibility of a large, multi-center randomized controlled trial by conducting a multi-center pilot trial comparing a protocolized daily assessment of readiness for liberation from VV-ECMO (ECMO-free protocol) to usual care. The success of the pilot trial will be measured by meeting specified benchmarks for enrollment, randomization, adherence to group assignment, and separation between groups. Secondary aim: To define and estimate the frequency of the primary efficacy, primary safety, and secondary outcomes of a future large, multi-center randomized controlled trial comparing a protocolized daily assessment of readiness for liberation from VV-ECMO (ECMO-free protocol) to usual care. To address these aims, we propose a multi-center, open-label, parallel-group, randomized pilot trial comparing a protocolized daily assessment of readiness for liberation from VV-ECMO (ECMO-free protocol) to usual care. All patients who receive VV-ECMO in a participating unit of an adult hospital and meet all inclusion criteria and no exclusion criteria will be eligible for participation. Eligible participants or surrogate decision makers will be approached for consent. Following documentation of written informed consent, patients will be enrolled and randomly assigned to receive the ECMO-free protocol or usual care. The study will control VV-ECMO weaning strategy until the first of decannulation or death. All other decisions regarding critical care support, interventional therapies, and medical treatment will remain at the discretion of the treating physician and consulting teams.

Official Title
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ECMO-Free Trial: A Multicenter Pilot Feasibility Study

Conditions
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Extracorporeal Membrane Oxygenation Complication

Intervention / Treatment
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* Other: ECMO-free protocol
* Other: Usual Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient receiving VV-ECMO Patient is located in a participating unit of an adult hospital Exclusion Criteria: Patient is pregnant Patient is a prisoner Patient is < 18 years old Participant is receiving ECMO as bridge to transplant Participant is receiving a hybrid configuration that includes an arterial cannula Patient has received VV-ECMO for > 24 hours

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, parallel-group, randomized pilot trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The ECMO-free Protocol group<br>For patients assigned to the ECMO-free protocol group, the study personnel will perform the ECMO-free protocol daily from enrollment until the first of death or ECMO decannulation; results will be recorded and shared with the treatment team. Final decisions regarding decannulation will be made by treating clinicians who are aware of the results of daily ECMO-free protocolized assessments. | Other: ECMO-free protocol<br>* All patients randomized to the ECMO-Free Protocol Group will receive a protocolized daily assessment of readiness for liberation from VV-ECMO, which will be initiated between 6:00 AM local time and 10:00 AM local time. If the patient is enrolled after 10:00 AM local time the ECMO-free protocol will begin the following calendar day. The ECMO-Free Protocol is a 3-step process of assessing readiness for liberation from VV-ECMO: a safety screen (Phase 1: ECMO-Free Safety Screen), titration of the non-ECMO fraction of inspired oxygen (Phase 2: Non-ECMO respiratory support titration), and a trial of cessation of sweep gas flow (Phase 3: ECMO-Free Trial).<br>|
| Active Comparator: The Usual Care Group<br>For patients assigned to the usual care group, ECMO weaning and assessments of readiness for ECMO decannulation will be at the discretion of treating clinicians. | Other: Usual Care<br>* All patients randomized to the Usual Care Group will undergo assessments of readiness for liberation, weaning, and decannulation at the discretion of the treatment team.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 60-day ECMO-free days | 60 minus the number of days from randomization to final decannulation with patients who die before the first of day 60 or hospital discharge receiving 0 ECMO-free days | From randomization to until the date of death or final decannulation, whichever came first, through study completion, an average of 2 years. | 
| Unsafe liberation from VV-ECMO | Criteria met within 48 hours of decannulation: VV-ECMO recannulation, sustained (> 4 hours) escalation of mechanical ventilation (change from a partially assisted mode to controlled MV, or dynamic driving pressure greater than or equal to 16 and delta change from previous setting of greater than or equal to 5 cm H2O, or increase in FiO2 to > 80%), use of rescue therapies (i.e. new need for paralysis and deep sedation, or inhaled pulmonary vasodilators, or high frequency oscillatory ventilation, or new worsening hemodynamics requiring addition of any vasoactive agents with no evidence of sepsis or hypovolemia) | From randomization to until the date of death or the date 24 hours after decannulation, whichever came first, through study completion, an average of 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of ECMO | Time from randomization to decannulation | From randomization to until the date of death or the date of decannulation, whichever came first, through study completion, an average of 2 years. | 
| Survival to decannulation | Alive at time of decannulation | From randomization to the date of death or decannulation, whichever came first, through study completion, an average of 2 years | 
| ICU-free days | Number of days alive and not in the ICU between randomization and day 60. | From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years. | 
| Ventilator-free days | Number of days alive and free from mechanical ventilation between randomization and day 60. | From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years. | 
| Hospital-free days | Number of days alive and not in the hospital between randomization and day 60. | From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years. | 
| In-hospital mortality | Death prior to hospital discharge. | From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years. |