Safety and Efficacy of Low-Flow ECMO in a Multi-modal Cohort of Adults in Respiratory Failure
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Ventilator-free days
研究概览
简要总结
The current standard of care (SOC) for treatment of patients with acute respiratory distress syndrome (ARDS), inhalation injury, volume overload, and/or pulmonary dysfunction is mechanical ventilation (MV). However, these techniques are associated with several complications after prolonged use, including risk of infection, increased sedation requirements, pulmonary edema, ventilator-induced lung injury (VILI), barotrauma, and multi-organ failure.
Extracorporeal life support (ECLS) has been used to successfully minimize, replace, or avoid the use of MV. This concept is critical as it permits ultra-lung protective MV settings, mobilization, early ambulation of patients, and timely extubation (when appropriate).
Conventional ECLS typically requires blood flows of 3-6 L/min, and its cannula sizes range from 21-25 Fr. This is by definition "high-flow" as it constitutes near-complete extracorporeal circulation of patient's circulating blood volume. On the other hand, low-flow ECLS at 1-2.5 L/min has been shown to prevent deleterious shifts in pH and PaCO2 at a lower level of invasiveness, and its cannula sizes range from 19-20 Fr dual lumen cannulas (which are associated with less serial dilation). The investigators propose the use of a low-flow circuit to include the NovaLung system in conjunction with a smaller tubing set and cannula to enable earlier utilization of ECLS with less invasiveness and smaller catheters. Specifically, the study will either utilize the Crescent RA cannula (or equivalent dual-lumen cannula) or use a 15-25 Fr cannula, both with 3/8 tubing/step-down tubing, as needed, for our study. A femoral (fem)-femoral or femoral-internal jugular (IJ) approach may also be used.
Carbon dioxide is six times more diffusible than oxygen across the membrane; thus, carbon dioxide transfers can occur with high efficiency at our targeted blood flows of 1-2.5L/min. Oxygen can still transfer at these blood flows, and low flow can improve oxygen levels to some degree.
There are three benchtop-based manuscripts that suggest that low-flow ECMO is associated with a potential increase in factors that increase the risk of bleeding complications/circuit changes. However, the manuscripts either tested <1 L/min blood flow rates, or the effect of cannula size was not considered. None of them included the biological component of endothelial interaction. Mitigating the risk of bleeding complications by will be completed by administering anticoagulants with a target PTT of 40-50 seconds, and by monitoring the patients and their coagulation panels closely. There may be less risk of circuit clotting in our study because of chosen flow rates (1-2.5 L/min).
详细描述
The investigators focus is to demonstrate the safety, feasibility, and efficacy of low-flow ECLS as a treatment for multiple respiratory conditions (including ARDS, volume overload, obstructive and restrictive pulmonary diseases, hypoxia) in conjunction with MV.
BACKGROUND
The two most significant trials in the last five years investigating strategies around low-flow ECLS with the intent of CO2 reduction/ventilator reduction are as follows:
- SUPERNOVA Multi-Center Phase II Study in Europe and Canada: In 2019 Combes et al assessed the feasibility and safety of lower CO2 extraction ECLS devices (300-500 mL/min) in patients with moderate ARDS compared to higher CO2 extraction ECLS devices (800-1000 mL/min, N=95). The authors concluded that the use of low-flow ECLS to facilitate ultra-protective ventilation was feasible, and that it mitigated respiratory acidosis in patients with moderate ARDS.
- REST Multi-Center Randomized Clinical Trial (RCT) in the United Kingdom: In 2021 McNamee et al set to determine whether lower tidal volume MV using extracorporeal CO2 removal improves outcomes in adult patients with acute hypoxemia respiratory failure (n=202) compared to conventional low tidal volume MV (n=210). There were significantly fewer mean ventilator-free days in the extracorporeal CO2 removal group compared with the SOC (p=0.02). However, the trial was halted because of futility and feasibility. Although the conclusion was that the use of extracorporeal CO2 removal did not significantly reduce 90-day mortality (p=0.68), the study may have been underpowered to detect an important difference. Furthermore, the most notable limitation of the study was that the duration of low-flow ECLS was limited to less than 7 days (which caused discontinuation of the intervention in 33 patients). The authors state that "it is possible that a longer duration of ECCO2R with greater tidal volume reduction may have been required to demonstrate an effect because higher intensities of invasive MV have been shown to be associated with increased risk of death in a time-dependent fashion". Additional limitations of the study were that (1) only 6% of the screened patients were included in the study, (2) 8% of the randomized subjects in the intervention group did not receive the intervention, and (3) most of the sites had not performed ECLS before the initiation of the study, leading to practical inexperience potentially negatively influencing the outcomes of the intervention group.
The investigators note several differences in their protocol that differentiates it from the REST trial. First, the investigators will use a device capable of obtaining higher blood flow rates with higher initial targets of blood flow (1-2.5L/minute). Specifically, the study will use a low-flow circuit to include the NovaLung system (Fresenius Medical Care, Waltham MA) in conjunction with a smaller tubing set and cannula (15 - 25 Fr versus 23 - 31 for conventional ECMO, as needed) to enable earlier utilization of ECLS with less invasiveness and smaller catheters. Second, the current study includes broader limitations to length of time of the device (e.g. 28 days versus 7 days), which may be a more pragmatic and generalizable approach.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Device Feasibility
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Acute hypoxemic respiratory failure meeting all the following criteria:
- •New or worsening respiratory symptoms developing within 2 weeks prior to the onset of need for oxygen or respiratory support
- •Endotracheal mechanical ventilation for ≤ 5 days
- •PaO2/FiO2 ≤ 200 mmHg for at least 6 hours, or for at least two readings one hour apart
- •Male or non-pregnant female
- •Admitted to the ICU at MHS
- •Age ≥ 18 years
排除标准
- •Hypoxemia is primarily attributable to fluid overload from acute heart failure
- •Hypoxemia is primarily attributable to pulmonary embolism
- •Hypoxemia is primarily attributable to status asthmaticus
- •Extubation is planned or anticipated on the day of screening
- •ICU discharge is planned or anticipated on the day of screening
- •The patient is moribund and deemed unlikely to survive past 24 hours (as determined by the clinical team)
- •The patient has limited code status, ordered for comfort measures only, or is in hospice
- •Patients over 65 years of age
- •Currently receiving any form of ECLS (ex. veno-venous, veno-arterial, or hybrid configuration)
- •ΔPL-dyn ≤ 20 or Static ΔP ≤ 15 cm H2O while receiving VT 6 mL/kg (i.e. normalized elastance < 2.5 cmH2O/mL/kg)
- •Chronic hypercapnic respiratory failure defined as PaCO2 > 60mmHg in the outpatient setting
- •Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not CPAP
- •Severe hypoxemia with PaO2:FiO2 < 80mmHg for >6 hours at time of screening
- •Severe hypercapnic respiratory failure with pH < 7.15 and PaCO2 > 60mmHg for >6 hours at time of screening
- •Expected mechanical ventilation duration < 48 hours at time of screening
- •Confirmed diffuse alveolar hemorrhage from vasculitis
- •Contraindications to limited anticoagulation (ex. active GI bleeding, bleeding diathesis)
- •Respiratory failure known or suspected to be caused by COVID-19
- •Cirrhosis of the liver (as classified stage C of the Child-Pugh Score)
- •Pregnancy
- •Inability to tolerate extracorporeal therapy (MAP<65 mmHg despite fluid resuscitation and vasopressors)
- •Unable to obtain informed consent from either patient or legally authorized representative (LAR)
研究组 & 干预措施
Initiation of low-flow ECLS
To evaluate the safety, feasibility, and efficacy of low-flow ECLS and assess the feasibility of its use
干预措施: Low-flow ECMO (Device)
结局指标
主要结局
Ventilator-free days
时间窗: Documented at 28 Days
Ventilator-free days in the first 28 days
次要结局
- Length of Stay (LOS)(Documented at discharge from the hospital, through study completion (an average of 21 days))
- Mortality(Documented at occurrence or death, or at discharge from the hospital, through study completion (an average of 21 days))
- Duration(Documented daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Conversion(Documented daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Adverse Events(Documented at occurrence, or daily at minimum through study completion, through study completion (an average of 21 days))
- Anticoagulation(Documented daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Cardiopulmonary variables: Tidal Volume(Documented hourly and daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Cardiopulmonary variables: Minute Ventilation(Documented hourly and daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Cardiopulmonary variables: Respiratory Rate(Documented hourly and daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Cardiopulmonary variables: Heart Rate(Documented hourly and daily throughout hospitalization until discharged, through study completion (an average of 21 days))
- Cardiopulmonary variables: Arterial Blood Gas(Documented as needed for clinical care (typically Q6) throughout hospitalization until discharged, through study completion (an average of 21 days))
- Inflammatory Markers(Pre-ECMO, daily on ECMO, at decannulation, and at 30/60/90 day follow-up apointments)
- Length of Stay (LOS)(Documented at discharge from the ICU, through study completion (an average of 21 days))
研究者
Jeffrey DellaVolpe
Medical Director, Institute for Extracorporeal Life Support; Intensivist
Institute for Extracorporeal Life Support