Prospective Randomized Trial of Total Lung Protective Ventilation in Adult VV-ECMO Patients With Severe ARDS

Pilot Trial Evaluating a Mechanical Power Targeted Ventilation Strategy in Adult VV ECMO Patients With Severe ARDS

The purpose of this study is to find a better way to protect the lungs of patients with Acute Respiratory Distress Syndrome (ARDS) who are being treated with a mechanical ventilator in addition to an extracorporeal membrane oxygenation (ECMO) machine. ARDS is a serious lung condition that makes it hard to breathe. People with ARDS often need care in the intensive care unit (ICU) and can become very sick with high mortality rates despite optimal care.

Doctors usually support patients with through ARDS with a breathing machine called a ventilator. The ventilator helps lungs imitate taking small breaths to help protect the lungs from more damage, however ventilator induced lung injury (VILI) can still contribute significantly to organ injury.

For patients in whom a ventilator is not enough support due to the severity of their lung disease, veno-venous (VV) ECMO can fully support the lungs while they recover. In these sickest patients, it is important to avoid causing more lung damage with the ventilator. Protecting the lungs may help them heal faster and may also help protect other parts of the body. More people are now being treated with VV ECMO, but there is still not enough research to know which ventilator settings are safest and work best. Most current recommendations are based on doctors' experience instead of research studies. This study will help researchers learn the best way to use ventilators for patients on VV ECMO and improve their recovery.

Acute respiratory distress syndrome (ARDS) is a common intensive care unit (ICU) admission diagnosis with mortality nearing 50% in severe cases. Traditional management focuses on lung protective ventilation consisting of low tidal volumes while limiting plateau and driving pressures. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a guideline recommended intervention for patients with severe ARDS refractory to other interventions. The optimal lung protective ventilation strategy for patients supported by VV-ECMO is unknown.

Over the past few decades, significant effort in the form of multiple international, multicenter, randomized controlled trials have evaluated lung protective ventilation strategies in ARDS, highlighted by the ARMA trial which showed an 8.8% absolute mortality reduction with low tidal volume ventilation and limiting plateau pressure to <30 cmH2O compared to standard of care at the time. These trials have helped define lung protective ventilation parameters over the past few decades, leading to significant improvements in mortality over that time. For patients with respiratory failure refractory enough to require VV ECMO support, avoiding further ventilator induced lung injury (VILI) is paramount to optimize the chances of lung recovery and avoid extrapulmonary organ dysfunction. However, despite the rapid increase in the utilization of VV ECMO for severe respiratory failure, very little prospective or randomized research has attempted to evaluate what constitutes lung protective ventilation in this patient population. In the absence of any current randomized trial evidence, management guidelines rely on expert opinion alone. These guidelines are extrapolated from lung protective ventilation studied in patients undergoing conventional mechanical ventilation despite significant differences introduced by the presence of the ECMO circuit, most notably the ability of the circuit to assume most if not all of the pulmonary support while enabling ultra-low tidal volume "lung rest" ventilation with tidal volumes of 3-4 cc/kg predicted body weight (PBW), limiting plateau pressures to ≤ 24 cmH2O but no greater than 30 cmH2O, and maintaining a respiratory rate of 4-15 breaths/minute but no greater than 30. Notably, the largest prospective observational trial of patients supported by VV ECMO for respiratory failure did not suggest an outcome benefit for any of these single traditionally targeted ventilator variables. Given the increasing utilization of VV ECMO for ARDS, there is a need for prospective evaluation of a more comprehensive approach to ventilator management as a means to minimize VILI and improve outcomes in this critically ill patient population.

Mechanical power (MP) attempts to more comprehensively unify all ventilator-related causes of lung injury such as distending pressure, tidal volume, flow, and respiratory rate into a single, quantifiable variable. Thus, MP is an innovative approach to more comprehensively reducing VILI compared to traditional tidal volume or plateau targets, providing a potential new benchmark for enhanced lung-protective ventilation. MP has been independently associated with poor patient outcomes even with low tidal volume and driving pressure in multiple studies in patients with and without ARDS, as well as ECMO and non-ECMO supported patient populations across numerous retrospective and observational studies. However, despite this strong correlation, the feasibility of prospectively evaluating a MP-based strategy in a randomized fashion remains unknown. The aim of this trial is to evaluate the feasibility, safety, and tolerability of a MP-targeted ventilation protocol in patients with severe ARDS requiring VV ECMO support as the first step in ultimately evaluating the ability of such a strategy to directly impact and improve patient-oriented outcomes.

Description of Study Intervention:

After randomization, patients will subsequently be assigned to either a low mechanical power target (2-4 J/min) or usual care. This range was chosen as it closely mirrors the power of normal breathing in healthy subjects and falls on the lower range of that reported in retrospective and observational trials, indicating potential feasibility. As a part of the protocol, patients in both arms will meet the current standard of care regarding the individual parameters of ultra-lung protective ventilation and "lung rest" while on VV-ECMO as it is currently defined. The low mechanical power target arm will follow a well-defined mechanical ventilator management algorithm to meet the assigned target, as described below. Patients in the usual care arm will be managed at the discretion of the treating intensivist with care, including mechanical ventilation settings, sedation, VV ECMO, and additional adjunct therapies, reflecting current best practice guidelines.

For patients assigned to the intervention arm, the patient will be placed on volume control (VC) or pressure control (PC) ventilation with either an initial tidal volume of 3-4cc/kg predicted body weight (PBW) (for VC) or inspiratory pressure required to reach the same tidal volume goal (for PC), FiO2 set between 0.30-0.50, and a PEEP of at least 10. This tidal volume or inspiratory pressure, for VC and PC ventilation respectively, will then be titrated down to meet a goal plateau pressure of less than or equal to 24 cmH2O, and a target driving pressure no greater than 14 cmH2O. Finally, the respiratory rate will then be titrated between 1 and 15 to meet the specified mechanical power goal range. Once the respiratory rate has been lowered to 8, tidal volumes (or inspiratory pressure required to meet this goal) will be lowered to 3cc/kg PBW prior to further reductions in respiratory rate. MP will be calculated every two hours and adjusted as needed to stay within the goal MP range until pre-specified weaning criteria are met.

Inclusion Criteria

1. On VV ECMO for less than 24 hours at time of study consent

2. Severe ARDS as the primary etiology of respiratory failure defined by:

   • Acute onset: Within 1 week of known clinical insult
   • Bilateral infiltrates: Evidence of fluid/inflammation in both lungs on X-ray, CT, or US, not fully explained by cardiac failure or fluid overload
   • Origin of Edema: Respiratory failure not fully explained by cardiac failure or fluid overload
   • Oxygenation impairment (Severe): PaO2/FiO2 ≤ 100 mm HG (Partial pressure of arterial oxygen/Fraction of inspired oxygen)

3. Age 18 or greater

Exclusion Criteria

1. Have received ECMO for >24 hours
2. Are on VV ECMO but are not mechanically ventilated, or are planned not to have/not require invasive mechanical ventilation for >24 hours
3. Patient is pregnant
4. Patient is a prisoner
5. Receiving VV ECMO as a bridge to transplant or history of lung transplant
6. History of pneumectomy or lobectomy
7. Age < 18
8. Are on any hybrid configuration of ECMO including an arterial limb (i.e., VAV, VVA, VA, etc.)