Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04903262 |
| Other study ID # |
SUPERNOVA |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2024 |
| Est. completion date |
March 31, 2026 |
Study information
| Verified date |
November 2023 |
| Source |
University of Bologna |
| Contact |
Tommaso Tonetti, M.D. |
| Phone |
+39-0512143268 |
| Email |
tommaso.tonetti[@]unibo.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
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.
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.
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.
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.
PROCEDURES
CONTROL GROUP
- Patients will be treated with the following conventional ventilator settings
("standardized ventilation"): mode of mechanical ventilation: volume assist/control; VT
= 6 mL/kg (PBW); inspiratory flow will be set at 50-70 L/min resulting in an
end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3; set RR to 20-35 bpm; PEEP
will be set according to the "lower PEEP/FiO2" table:
- PBW will be calculated according to the following formulae: PBW (Males) = 50 + 0.91
[height (cm)-152.4]; PBW (Females) = 45.5 + 0.91 height (cm)-152.4].
- Oxygenation Goal: PaO2 55-80 mmHg or SpO2 88-95%;
- Arterial pH Goal: 7.30-7.45.
- It is recommended to perform 2 daily lung recruitment maneuvers (as per standard
clinical practice in each center).
- Patients may receive NMBA and continued as directed by the attending physician.
- Use heated humidifiers for gas humidification and minimize instrumental dead space.
TREATMENT GROUP
- Patients will be treated with the following conventional ventilator settings
("standardized ventilation"): mode of mechanical ventilation: constant flow, volume
assist/control; VT = 6 mL/kg (PBW); inspiratory flow will be set at 50-70 L/min
resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3; set RR to
20-35 bpm; PEEP will be set according to the "lower PEEP/FiO2" table:
- PBW will be calculated according to the following formulae: PBW (Males) = 50 + 0.91
[height (cm)-152.4]; PBW (Females) = 45.5 + 0.91 height (cm)-152.4].
- Oxygenation Goal: PaO2 55-80 mmHg or SpO2 88-95%;
- Arterial pH Goal: 7.30-7.45.
- Patients may receive NMBA and continued as directed by the attending physician.
- Use heated humidifiers for gas humidification and minimize instrumental dead space.
- ECCO2R will be initiated during "standardized ventilation".
- Catheterization for ECCO2R will be performed according to local institutional clinical
practice. The ECCO2R circuit will be connected to the catheter and blood flow set
between 1000 and 1500 mL/min. Initially, sweep gas flow through the ECCO2R device will
be set at zero (0 LPM) such as to not initiate CO2 removal through the device.
Anticoagulation will be maintained with unfractionated heparin to a target aPTT of 1.5 -
2.0x baseline. A bolus of 80 I.U./kg unfractionated heparin is suggested at the time of
cannulation.
- The objective is to maintain PaCO2 at baseline value ± 20% of baseline settings obtained
with a VT = 6 mL/kg provided that pH remains ≥ 7.30. End-tidal CO2 (EtCO2) will be
monitored for safety purposes.
- REDUCTION OF VT: Following a run-in time (up to a maximum of 2 hours) with sweep gas
flow at zero LPM, VT will be reduced gradually to 5 mL/kg. Sweep gas will be initiated
and VT decreased to 4.5 then 4 mL/kg, and PEEP adjusted to maintain the same mean airway
pressure as during standardized ventilation, provided that Pplat ≤ 25 cmH2O (i.e., if
the PEEP level required to maintain mean airway pressure leads to a Pplat > 25 cmH2O,
PEEP is then reduced until a Pplat ≤ 25 cmH2O).
- It is recommended to perform 2 daily lung recruitment maneuvers (as per standard
clinical practice in each center).
- REDUCTION OF RESPIRATORY RATE: Respiratory rate will be progressively decreased to a
minimum of 8 bpm and facilitated by increases in sweep gas flow; a constant I:E ratio
will be maintained.
- 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.
- CO2 removal will be performed using the following device, routinely used for clinical
purposes in each site:
- HLS5.0 Cardiohelp® (Getinge Cardiopulmonary Care, Rastatt, Germany): 1.3 m²
polymethylpentene hollow fiber membrane oxygenator will be used, combined with HLS sets
(BIOLINE heparine-coating). 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.
INTERRUPTION OF TREATMENT According to group assignment, "standardized ventilation" or "ultra
protective ventilation + ECCO2R" will be maintained for at least 72 hours; then, interruption
trials according to protocol will be performed every 24 hours, until liberation from
mechanical ventilation and ECCO2R. In the treatment group, patients will be always weaned
first from ECCO2R and subsequently from mechanical ventilation.
Interruption trials will be performed after at least 72 hours of study enrollment if all the
following criteria are met: 1) PaO2/FiO2 > 250 with PEEP 8-10 cmH2O and FiO2 <0.5; 2) values
of both PEEP and FIO2 ≤ than values from previous day; 3) the patient is not receiving
neuromuscular blocking agents; 4) the patient is exhibiting inspiratory efforts; 5) systolic
arterial pressure ≥ 85 mmHg without vasopressor and/or inotropic support (≤ 5 mcg/kg/min
dopamine or dobutamine will not be considered inotropic support in this context).
In the CONTROL group, in presence of all criteria 1-5, a spontaneous breathing trial will be
conducted every 24 hours, until liberation from mechanical ventilation (see "weaning
procedures" below).
In the TREATMENT group, in presence of all criteria 1-5, a zero-sweep gas trial will be
conducted every 24 hours: sweep gas will be deactivated for 6 hours and then presence of all
criteria 1-5 will be checked again; if still all present, ECCO2R will be removed and further
weaning from mechanical ventilation will be conducted as in the control group.
RESCUE THERAPIES
- Refractory hypoxemia will be defined as PaO2 < 60 mm Hg for at least 1 hour while
receiving an FIO2 of 1.0
- Refractory acidosis will be defined as pH ≤ 7.10 for at least 1 hour
- Refractory barotrauma will be defined as persistent pneumothorax with 2 chest tubes on
the involved side or increasing subcutaneous or mediastinal emphysema with 2 chest
tubes.
If refractory hypoxemia OR refractory acidosis OR refractory barotrauma occurs, the events
surrounding this event(s) will be recorded and clinicians at their discretion may deviate
from the assigned ventilation protocols and institute so-called rescue therapies, including:
inhaled nitric oxide, prone position, extracorporeal membrane oxygenation (ECMO). The use of
these therapies will be recorded in the study case report forms.
WEANING PROCEDURES
- A Spontaneous Breathing Trial (SBT) procedure and assessment for unassisted breathing
will be performed: 30 - 120 minutes of spontaneous breathing with FIO2 < 0.5 using any
of the following approaches: Pressure support (PS) < 5 cmH2O, PEEP < 5 cmH2O; CPAP < 5
cmH2O; T-piece; Tracheotomy mask
- Criteria to be met during the last 30 minutes of a SBT for reporting the SBT as
"SUCCESSFUL": SpO2 ≥ 90% and / or PaO2 ≤ 60 mm Hg; Respiratory Rate ≤ 35 / min; pH ≥
7.30; Absence of respiratory distress.
- If any of the above-mentioned criteria is not met, the SBT will be reported as
"UNSUCCESSFUL" and previous ventilator settings or to PS greater than or equal to 10 cm
H2O with PEEP and FIO2 at the previous settings will be initiated. The patient will be
reassessed for weaning the following day.
- If the SBT is "SUCCESSFUL", ventilatory support will be removed.
- Patients will be reported as "VENTILATOR FREE" after two consecutive calendar days of
"UNASSISTED BREATHING". "UNASSISTED BREATHING" will be defined as any of the following:
Spontaneously breathing with face mask, nasal prong oxygen, or room air; T-tube
breathing; Tracheostomy mask breathing; CPAP ≤ 5 without PS or IMV assistance; use of
CPAP or BIPAP solely for sleep apnea management
