MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study

Abstract

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure.

Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO₂/FiO₂ ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis.

Results: tPA was associated with significant PaO₂/FiO₂ improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO₂/FiO₂ ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration.

Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population.

FIGURE 1

PaO₂/FiO₂ estimates over time. The value “‐4” in the x‐axis indicates the baseline PaO₂/FiO₂, collected 3–6 h before tPA was administered. The red bar marks the administration of tPA. (A) Unadjusted PaO₂/FiO₂; overall time effect p = 0.02, asterisks indicate significant differences compared with baseline. (B) PaO₂/FiO₂ estimates, adjusted for significant covariates (see text), stratified by the trend in pre‐tPA PaO₂/FiO₂ (significant effect modifier interaction time × pre‐tPA trend p < 0.00). Color‐concordant asterisks indicate significant differences compared with baseline. Only the group with declining PaO₂/FiO₂ showed significant differences compared with baseline. tPA, tissue plasminogen activator

FIGURE 2

Ventilatory ratio (correlate of dead space) estimates over time. The value “‐4” in the x‐axis indicates the baseline ventilatory ratio, collected 3–6 h before tPA was administered. The red bar marks the administration of tPA. (A) Unadjusted ventilatory ratio; overall time effect p = 0.00, asterisks indicate significant differences compared with baseline. (B) Ventilatory ratio estimates after adjustment for significant covariates (see text) did not significantly change over time (p = 0.16) and the temporal trend was not modified by the pre‐tPA trend in ventilatory ratio (interaction time × pre‐tPA trend p = 0.15). tPA, tissue plasminogen activator

FIGURE 3

NEWS2 score estimates over time. The value “‐4” in the x‐axis indicates the baseline NEWS2 score, collected 3 to 6 hours before tPA was administered. The red bar marks the administration of tPA. (A) Unadjusted NEWS2 score; overall time effect p < 0.00, asterisks indicate significant differences compared with baseline. (B) NEWS2 score estimates after adjustment for significant covariates (see text), stratified by the trend in pre‐tPA NEWS2 score (significant effect modifier interaction time × pre‐tPA trend p = 0.001). Color‐concordant asterisks indicate significant differences compared with baseline. Only the group with increasing NEWS2 score showed significant differences compared with baseline. NEWS2, National Early Warning Score 2; tPA, tissue plasminogen activator

FIGURE 4

D‐dimer and fibrinogen levels before and after tPA administration. (A) Unadjusted D‐dimer values over time (time effect p < 0.00). The value “‐4” in the x‐axis indicates the baseline D‐dimer, collected 3–6 h before tPA was administered. The red bar indicates the tPA administration. Asterisks denote significant differences compared with baseline. (B) Fibrinogen values over time (time effect p = 0.02). The value “‐4” in the x‐axis indicates the baseline D‐dimer, collected 3–6 h before tPA was administered. The red bar indicates the tPA administration. Asterisks denote significant differences compared with baseline. tPA, tissue plasminogen activator