At the beginning COVID-associated lung injury was considered as typical ARDS, hence respiratory and nonrespiratory treatments were delivered according to general principles for this kind of illness. There is hypothesis that in predisposed individuals, alveolar viral damage is followed by an inflammatory reaction and by microvascular pulmonary thrombosis. The investigators suggest that thrombolytic therapy may be beneficial when compared to standard care in patients with SARS-CoV-2 and severe respiratory failure.
COVID 19 pandemic is a serious challenge for International medical community. There is lack
of knowledge about the nature and character of the lung injury caused by this kind of
infection. At the beginning COVID-associated lung injury was considered as typical ARDS,
hence respiratory and nonrespiratory treatments were delivered according to general
principles for this kind of illness. There is hypothesis that in predisposed individuals,
alveolar viral damage is followed by an inflammatory reaction and by microvascular pulmonary
thrombosis. This progressive endothelial thromboinflammatory syndrome may also involve the
microvascular bed of the brain and other vital organs, leading to multiple organ failure and
death. Understanding the crucial role of microthrombosis in the genesis of SARS-2-CoV led to
a widespread anticoagulant use. Moreover, there is evidence about a possible benefit of
thrombolysis in patients with severe COVID-19 pulmonary disease. For Instance, some
investigators reported about three patients with COVID 19 lung injury treated with alteplase
(tPA). Authors oversaw positive changes in P/F ratio in 3/3 patients, even if in two of these
patients changes lasted for a short period. Another investigators reported about the
improvements in alveolar ventilation, arterial oxygenation and diminishing in vasopressor's
support in 4 patients with SARS-2CoV after thrombolysis. Encouraging results were obtained
also by another team in case series of 5 patients who received alteplase. Thus, there is
evidence suggesting that thrombolytic therapy may be beneficial when compared to standard
care in patients with SARS-CoV-2 and severe respiratory failure. This hypothesis is based on
a well-established pathophysiological concept of the occurrence of pulmonary damage as a
result of microthrombosis of the lung vessels. Hence, it seems crucial to conduct a
randomized clinical trial to test the effectiveness of this treatment.
Objective: To establish whether plasminogen activator (tPA) treatment improves alveolar
ventilation P/F (PaO2/FiO2) ratio will be calculated each 6 hours during first 3 days after
the end of thrombolysis procedure in patients with an Atypical Acute Respiratory Distress
Syndrome (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome
(MicroCLOTS).
Methods: Research assistants and/or clinician screen all mechanically ventilated patients for
eligibility. Patients satisfying all of the Inclusion and Exclusion Criteria are classified
as 'Eligible'. With informed consent from a substitute decision maker or under the decision
of Concilium of three independent physicians, Eligible patients are 'Enrolled' into the
study. Eligible patients Qualify for Randomization to one of the 2 groups: with or without
thrombolytic therapy. In summary, patients are consented and Enrolled prior to Randomization.
To enroll or randomize Eligible patients, research coordinators obtain informed consent and
access the automated web-based system through Internet based program (available 24
hours/day). Each participating center has a separate computer-generated randomization
schedule, with 1:1 (control to intervention) assignment, stratified by center, and using
random variable block sizes.
The thrombolysis procedure: In the study group, tPA (Alteplase) 25 mg i/v over 2 hours,
followed by a 25 mg tPA infusion over the subsequent 22 hours. After the end of thrombolytic
therapy, unfractionated heparin is administered i/v at a starting dose of 10 units / kg per
hour. The target value of PTT is 40C-50C. In the control group, an equivalent amount of
Ringer's solution is administered. After 24 hours, the heparin infusion gets started, similar
the described for study group.
In both groups patient's transfer from the heparin infusion to the introduction of
low-molecular-weight heparins is performed after normalization of the D-dimer level.
Statistical analysis: Primary data analysis will be based on intention to treat (ITT)
analysis.
Data will be analyzed also on a modified ITT approach (mITT). Will be included in this
analysis only patients with evidence of an Atypical Acute Respiratory Distress Syndrome
(Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome (MicroCLOTS).
Subgroups analysis: Some pre-defined subgroups analysis will be performed:
1. Patients with with P/F <200 mmHg>100 mmHg;
2. Patients with with P/F <100 mmHg;
3. Patient 65+ group;
4. Patients under 65 years old. Interim analyses: Interim analyses will not be performed
Drug: Tissue plasminogen activator
In the study group, tPA (Alteplase) 25 mg i/v over 2 hours, followed by a 25 mg tPA infusion over the subsequent 22 hours. After the end of thrombolytic therapy, unfractionated heparin is administered i/v at a starting dose of 10 units / kg per hour. The target value of PTT is 40C-50C.
In both groups patient's transfer from the heparin infusion to the introduction of low-molecular-weight heparins is performed after normalization of the D-dimer level.
Other Name: Alteplase
Drug: Ringer solution
In the control group, an equivalent amount of Ringer's solution is administered. After 24 hours, the heparin infusion gets started, similar the described for study group.
In both groups patient's transfer from the heparin infusion to the introduction of low-molecular-weight heparins is performed after normalization of the D-dimer level.
Inclusion Criteria:
1. Severe pulmonary coronavirus disease 19 (COVID 19) with suspect for MicroCLOTS
(microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome)
2. P/F ratio <200 mmHg> 70 mmHg
3. a.) Contrast CT scan positive for pulmonary thrombosis, OR b.) Contrast CT scan
negative for pulmonary thrombosis:
- D-Dimer > 10 mcg/mL, OR
- 5 < D-dimer < 10 mcg/mL and C Reactive Protein (CRP) > 100 mg/dL
Exclusion Criteria:
- Age < 18
- Pregnancy or breastfeeding
- Known allergy to iodinated contrast dye
- Severe vasoplegic shock: norepinephrine > 300 ng/kg*min
- Glomerular Filtration rate < 30 ml/min
- Active bleeding or absolute contraindication to anticoagulant therapy (Stroke
(intracranial hemorrhage, hemorrhagic stroke), including a history of the last 6
months.; cancer of the Central nervous system and other localities with an increased
risk of bleeding, vascular aneurysm, traumatic open heart massage, obstetric delivery,
General operations, severe uncontrolled hypertension, gastric ulcer and 12-duodenal
ulcer (for 3 months. from the moment of exacerbation), arterial or venous
malformations, liver failure, liver cirrhosis, portal hypertension, esophageal
varicose veins, active hepatitis).