SUPERNOVA: Ultra-Protective Lung Ventilation With Extracorporeal CO2 Removal for Moderate ARDS
Study Details
Study Description
Brief Summary
Acute respiratory distress syndrome (ARDS) accounts for 10% of all ICU admissions and for 23% of patients requiring mechanical ventilation (MV). Its hospital mortality remains high, ranging from 34% in mild forms up to 46% in severe cases. Positive pressure MV remains the cornerstone of management, but at the same time it can contribute to worsening and maintenance of the lung injury when excessive stress and strain is applied to the lung parenchima (so-called ventilator-induced lung injury, VILI). VILI significantly contributes to the morbidity and mortality of ARDS patients, and it has been clearly demonstrated that protective (low-volume, low-pressure) MV settings are associated with a significant survival benefit. Unfortunately, in a certain proportion of ARDS cases, it is difficult to preserve acceptable gas exchange while maintaining protective ventilation settings, due to a high ventilatory load. In these cases, extracorporeal CO2 removal (ECCO2R) can be applied to grant the application of protective or even ultra-protective mechanical ventilation settings.
The main outcome of this multicenter, prospective, randomized, comparative open trial is to determine whether early ECCO2R allowing ultraprotective mechanical ventilation improves the outcomes of patients with moderate ARDS.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
- BACKGROUND
1.1 Acute respiratory distress syndrome (ARDS)
Acute respiratory distress syndrome (ARDS) represents a form of lung injury that occurs in response to various predisposing events, characterized by inflammation, increased pulmonary vascular permeability and loss of aerated lung tissue. The diagnosis of ARDS is based on severe hypoxemia and bilateral radiographic opacities occurring within 7 days of a known clinical insult or worsening respiratory symptoms. Central to the pathophysiology of ARDS is the presence of fibrin-rich exudates (hyaline membranes) due to activation of coagulation and inhibition of fibrinolysis. ARDS accounts for 10 % of all ICU admissions and for 23% of patients requiring mechanical ventilation (MV). Hospital mortality of ARDS patients remains high, ranging from 34% with mild ARDS, up to 46% with severe ARDS. Notably, severe and critical forms of coronavirus disease 2019 (COVID-19) are almost invariably associated with ARDS.
1.2 Ventilator Induced Lung Injury (VILI)
MV is a lifesaving form of support for patients with ARDS since it decreases the oxygen cost of breathing, improves gas exchange and provides time for resolution of the underlying etiology of ARDS. However, it has been consistently shown that MV may contribute to ventilator-induced lung injury (VILI) characterized by progression of pulmonary damage, worsening of the pulmonary inflammatory process, increased alveolar-capillary permeability and therefore leading to the translocation of inflammatory mediators from the lungs into the systemic circulation with consequent failure of distal organs (biotrauma). A randomized clinical trial showed that ventilating ARDS patients with a tidal volume (VT) of 6 ml/kg (calculated from predicted body weight, PBW), and with a maximum end-inspiratory plateau pressure (PPLAT) of 30 cmH2O decreased mortality from 40 % (seen in the conventional arm treated with a VT of 12 ml/kg PBW) to 31%. Recently, Amato and coworkers showed that the delta pressure (∆P), i.e. the difference between PPLAT and positive end-expiratory pressure (PEEP) (∆P = PPLAT -PEEP) ≤ 14 cmH2O was strongly associated with survival, demonstrating that interventions to obtain protective ventilatory settings (reductions in VT or increases in PEEP) were beneficial only if associated with decreases in ΔP.
1.3 Extra-corporeal CO2 Removal (ECCO2-R)
The use extracorporeal support to remove carbon dioxide (CO2) to permit the use of low volume/low pressure ventilation with minimal impact on PaCO2 was proposed in 1977. It was suggested that applying low VT and low peak inspiratory pressures ("lung rest") at a low respiratory rate could minimize damage to the compromised lungs. With this technique, oxygenation and removal of carbon dioxide were dissociated: oxygenation occurred predominantly through the lungs, and a variable portion of the carbon dioxide was removed through an artificial lung (extracorporeal CO2removal: ECCO2-R). The key potential advantage to this approach over extracorporeal membrane oxygenation (ECMO) is the use of lower blood flow through the extracorporeal circuit potentially with fewer side effects. Low VT ventilation (3-4 ml/kg of PBW) was associated with a significant decrease in inflammatory markers when compared with standard low volume, low pressure ventilation. Furthermore, the resulting hypercapnia was easily controlled by ECCO2-R. A randomized clinical trial showed that VT of 3 ml/kg of PBW was easy and safe to be implemented with extracorporeal CO2-removal. Clinical outcome, evaluated as days free from mechanical ventilation through day 28, significantly improved in ECCO2R patients compared to control, when analyzing patients with PaO2/FiO2<150.
A multicenter study designed to assess safety and feasibility of ECCO2R in ARDS showed that more than 80% of patients with moderate ARDS could achieve ultra-protective ventilation goals by using ECCO2R. The incidence of severe adverse events related to ECCO2R was low (~2%). Efficacy and safety of ECCO2R A was higher for devices that used blood flow rates in the range of 1000-1500 ml/min. A post-hoc analysis showed that restricting enrollment to patients with compliance of the respiratory system ≤ 40 ml/cmH2O and decrease in ∆P ≥ 5 cmH2O would increase predicted benefit in terms of clinical outcomes in a randomized clinical trial of VT of 3 ml/kg of PBW with ECCO2R (enrichment strategy). Moreover, recent data show that there is no safe upper limit for PPLAT or ΔP, consistent with the fact that since the mortality rate in ARDS patients with ΔP values ≤ 14 cmH2O is still as high as 20%. Patient outcomes may therefore be improved by aggressively lowering ventilatory variables such as VT, PPLAT, or ΔP as facilitated by ECCO2R devices that remove CO2. In addition, ECCO2R might further decrease VILI by allowing lower respiratory rates, which have been shown to be lung protective.
1.4 OBJECTIVE
The objective of this multicenter, prospective, randomized, comparative open trial is to determine if early ECCO2R allowing ultraprotective mechanical ventilation (VT 4 ml/kg) improves the outcomes of patients with ARDS.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ECCO2R Patients will be treated with "standardized ventilation": constant flow, assist/control; VT = 6 mL/kg PBW; insp. flow 50-70 L/min, I:E ratio 1:1 to 1:3; RR 20-35 bpm; PEEP according to "low PEEP/ high FiO2" table. Goals: PaO2 55-80 mmHg or SpO2 88-95%; arterial pH: 7.30-7.45. ECCO2R blood flow between 1000 and 1500 mL/min. Anticoagulation with unfractionated heparin to a target aPTT of 1.5 - 2.0x baseline. Target: maintain PaCO2 at baseline value ± 20% of baseline settings with a VT = 6 mL/kg provided that pH remains ≥ 7.30. Following 2-hour run-in time, VT will be reduced to 5 mL/kg. Sweep gas will be initiated and VT decreased to 4.5 then 4 mL/kg, and PEEP adjusted to reach 23 ≤ Pplat ≤ 25 cmH2O. Respiratory rate progressively decreased to a minimum of 12 bpm (eventual increases in sweep gas flow). If PaCO2 > 75 mmHg and/or pH < 7.2, despite respiratory rate of 35/min and optimized ECCO2R, VT will be increased to the last previously tolerated VT. |
Procedure: Ultraprotective ventilation with Extracorporeal CO2 removal
HLS5.0 Cardiohelp® (Getinge Cardiopulmonary Care, Rastatt, Germany): 1.3 m² polymethylpentene hollow fiber membrane oxygenator. The extracorporeal blood flow is in the range of 1000 to 1500 mL/min. Sweep gas (air or oxygen) is drawn through the hollow fibers by a vacuum pump, creating a diffusion gradient for gas exchange across the membrane.
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| No Intervention: Standard of care Patients will be treated with "standardized ventilation": constant flow, assist/control; VT = 6 mL/kg PBW; insp. flow 50-70 L/min, I:E ratio 1:1 to 1:3; RR 20-35 bpm; PEEP according to "low PEEP/ high FiO2" table. Goals: PaO2 55-80 mmHg or SpO2 88-95%; arterial pH: 7.30-7.45. |
Outcome Measures
Primary Outcome Measures
- Number of ventilator-free days (VFDs) at 28 days after randomization. [28 days]
VFD to-day 28 is defined as the number of days of unassisted breathing to day 28 after randomization, assuming a patient survives for at least two consecutive calendar days after initiating unassisted breathing and remains free of assisted breathing.
Secondary Outcome Measures
- 28-day all-cause mortality [28 days]
All patients will be classified as either "alive at Study Day 28" or, if dead, "dead at Study Day 28."
- 90-day all-cause mortality [90 days]
All patients will be classified as either "alive at Study Day 90" or, if dead, "dead at Study Day 90".
- Cumulative incidence of severe adverse events during 28 days after randomization [28 days]
Device-related and/or patient-related severe adverse events
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age > 18 years
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On invasive mechanical ventilation for ≤ 96 hours
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Presence of all of the following conditions for ≤ 24 hours: 100 < PaO2/FiO2 ≤ 200 after 12 hours of "standardized ventilation" with PEEP ≥ 5; compliance of the respiratory system ≤ 0.5 ml/cmH2O per kg PBW; bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules; respiratory failure not fully explained by cardiac failure or fluid overload
Exclusion Criteria:
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Pregnancy
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ARDS with PaO2/FiO2<100 or PaO2/FiO2>200 under standardized ventilation with PEEP ≥ 5 cmH2O
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Expected duration of mechanical ventilation < 48 hours
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Severe COPD
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Chronic respiratory insufficiency with home ventilation or oxygen therapy
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Currently receiving ECMO therapy
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Acute brain injury
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Severe liver insufficiency (Child-Pugh scores >7) or fulminant hepatic failure
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Heparin-induced thrombocytopenia
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Contraindication for systemic anticoagulation
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Platelet count <50,000/mm3
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Prothrombin time-international normalized ratio (INR) >1.5
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Patient moribund, decision to limit therapeutic interventions
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End-stage disease
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Unable to provide vascular access for ECCO2-R
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Acute coronary syndrome
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Actual body weight exceeding 1 kg per centimeter of height
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Burns > 40% total body surface
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Bone marrow transplantation within the last 1 year
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- University of Bologna
Investigators
- Study Chair: Marco Ranieri, M.D., University of Bologna
- Study Chair: Antonio Pesenti, M.D., University of Milan
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SUPERNOVA