COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis.

Patients with severe COVID-19 disease have been characterized as having the acute respiratory distress syndrome (ARDS). Critically ill COVID-19 patients have relatively well-preserved lung mechanics despite severe gas exchange abnormalities, a feature not consistent with classical ARDS but more consistent with pulmonary vascular disease. Many patients with severe COVID-19 also demonstrate markedly abnormal coagulation, with elevated d-dimers and higher rates of venous thromboembolism. We present four cases of patients with severe COVID-19 pneumonia with severe respiratory failure and shock, with evidence of markedly elevated dead-space ventilation who received tPA. All showed post treatment immediate improvements in gas exchange and/or hemodynamics. We suspect that severe COVID-19 pneumonia causes respiratory failure via pulmonary microthrombi and endothelial dysfunction. Treatment for COVID-19 pneumonia may warrant anticoagulation for milder cases and thrombolysis for more severe disease.

COVID-19 Critical Illness Pathophysiology Driven by Diffuse Pulmonary Thrombi and Pulmonary Endothelial Dysfunction Responsive to Thrombolysis.

Patients with severe COVID-19 disease have been characterized as having the acute respiratory distress syndrome (ARDS). Critically ill COVID-19 patients have relatively well-preserved lung mechanics despite severe gas exchange abnormalities, a feature not consistent with classical ARDS but more consistent with pulmonary vascular disease. Patients with severe COVID-19 also demonstrate markedly abnormal coagulation, with elevated D-dimers and higher rates of venous thromboembolism. We present five cases of patients with severe COVID-19 pneumonia with severe respiratory failure and shock, with evidence of markedly elevated dead-space ventilation who received tPA. All showed post treatment immediate improvements in gas exchange and/or hemodynamics. We suspect that severe COVID-19 pneumonia causes respiratory failure via pulmonary microthrombi and endothelial dysfunction. Treatment for COVID-19 pneumonia may warrant anticoagulation for milder cases and thrombolysis for more severe disease.

Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice.

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1-/-). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1-/- Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1-/-; however, minute diaphragm electromyogram activity increased in WT but not HO-1-/- The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1-/- CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1-/-, and 2) the baseline sympathetic activity in WT and HO-1-/-, which remained stable subsequently in WT but not in HO-1-/- We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.