At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Alteplase 50 MG [Activase]: Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but <50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Alteplase 50 MG [Activase]: Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but <50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Alteplase 50 MG [Activase]: Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but <50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Alteplase 50 MG [Activase]: Patients randomized to Alteplase-50 group will receive 50 mg of Alteplase intravenous bolus administration over 2 hours, given as a 10 mg push followed by the remaining 40 mgs over a total time of 2 hrs. Immediately following the Alteplase infusion, 5000 units (U) of unfractionated heparin (UFH) will be delivered and the heparin drip will be continued to maintain the activated partial thromboplastin time (aPTT) at 60-80sec (2.0 to 2.5 times the upper limit of normal). Re-bolusing of Alteplase, at the same dose, is permitted in the Alteplase-50 intervention group in those patients who show an initial transient response (>20% improvement of PaO2/FiO2 over pre-infusion of Alteplase at any of the measurements at 2, 6, 12 or 18 hours, but <50% improvement of PaO2/FiO2 at 24 hours after randomization); the repeat dose will be given between 24 and 36 hours after the initial Alteplase administration.

Patients randomized to Control arm will receive no study medication; the treatment will be standard of care according to the institution's protocol for ARDS.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 1 (patients 1 to 36): patients randomized to tPA-Bolus intervention received an intravenous (IV) 50mg bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours. Immediately upon completion of the tPA, a 5000 unit bolus of IV unfractionated heparin (UFH) was administered and continued for the next 7 days (or until extubation) as an infusion to maintain activated partial thromboplastin time (aPTT) of 60-80 seconds. At 24 hours after tPA initiation, patients with a PaO2/FiO2 improvement that was at least 20% but did not meet the primary endpoint of a 50% improvement (i.e., 20-49% improvement) and who did not develop any of the above-mentioned exclusion criteria, received a second 50mg tPA bolus, during when the UFH infusion was halted and resumed at its prior rate as soon as the second tPA administration was complete. The heparin regimen was maintained for seven days or until successful extubation.

At randomization, patients assigned to the control group continued their current medical care according to their institution's protocols, with no input from the study team.

Phase 2 (patients 37 to 50): patients randomized to the intervention received the tPA-Drip intervention consisting of a 50mg IV bolus of 1mg/mL tPA as a 10mg push followed by the remaining 40mg infused over the next 2 hours (not to exceed 0.9mg/kg dose). Immediately following this initial tPA infusion, patients received a drip of 2 mg/hr tPA over the ensuing 24 hours (total 48 mg infusion) accompanied by an infusion of a sub-therapeutic dose of 500U/hour of heparin during the tPA drip. Once the tPA drip terminated, the heparin dose was titrated up (no bolus) to maintain an aPTT 60-80 seconds.