Since its earliest presentation in late 2019, the incidence of the novel coronavirus (COVID-19) has dramatically increased.1–3 As COVID-19 has rapidly exhausted human and physical resources; clinicians and researchers strive to better understand the virus and how to combat its clinical manifestations.3,4 Most patients present with varying degrees of respiratory insufficiency; many will progress to respiratory failure with a severe version of acute respiratory distress syndrome (ARDS) refractory to traditional supportive strategies.5 Providers must consider alternative therapies to deter or prevent the cascade of decompensation to fulminant respiratory failure.3,4
As clinical observations accumulate, it is increasingly theorized that an exaggerated, prothrombotic state is associated with the systemic response mounted in defense against the virus.6–8 This prothrombotic state, induced by the response to systemic stress or shock has long been associated with thrombosis in the microvasculature of the lungs.9–12 It is theorized that this process further perpetuates inflammatory cell aggregation, worsens pulmonary edema, and decreases lung and alveolar compliance resulting in decreased oxygenation and ventilation.9–14 In the COVID-19–driven ARDS, the concept of an exaggerated, prothrombotic state is supported by various clinic findings. Cui et al.15 noted 25% of their patients with severe COVID-19 had developed venous thromboemboli.15 They further noted that a D-dimer of 1.5 μg/mL was sensitive and specific for predicting development of venous thromboembolism in these patients. A fourfold elevation in D-dimer from normal has been correlated with mortality in COVID-19 patients as was recently demonstrated by Tang et al.7 In their study of COVID-19 patients, an average D-dimer on admission of 0.6 μg/mL was noted in survivors while a four-fold increase was noted in nonsurvivors. Furthermore, recent autopsy reports conducted on COVID-19 patients describe significant platelet and inflammatory cell aggregation within the lung parenchyma as well as thrombi within the microvasculature.6 The combination of these clinical indicators of thrombosis, coupled with recent autopsy results, adds credence to the theory of microvascular thrombosis in the lungs contributing to the severe hypoxemia and ARDS-like picture that COVID-19 patients are demonstrating.
Thrombolytic therapy in ARDS has already been applied successfully in vivo. Hardaway et al.9–11,16 reported improvement in Pao2 values without deleterious effects in fulminant ARDS patients following administration of urokinase in the early 1990s. Thirty percent of these fulminant ARDS cases would go on to survive.16 The respiratory insufficiency related to COVID-19 has distinct features from that of a more classic ARDS.17 At this point in our understanding of the COVID-19 disease process, there appears to be a thrombosis burden in the lungs contributing to the severe hypoxemia that these patients demonstrate.6,7,15 The possibility of improving outcomes with thrombolytic therapy was highlighted by Moore et al.18 who proposed the use of tissue plasminogen activator (tPA) in COVID-19 patients. We report a series of five COVID-19 patients who underwent thrombolytic therapy. Herein, we describe our application of the therapy and our patient's clinical course and outcomes.
This retrospective review, case series report was granted exemption status by our Institutional Review Board. The COVID-19–positive patients were identified with severe hypoxia who were either on the ventilator or requiring noninvasive oxygenation. All patients had an elevated D-dimer value greater than 1.5 μg/mL and had no contraindications to thrombolytic therapy. For all patients, informed consent was obtained from either the patient or a family member and tPA was administered by the following protocol: a 25-mg tPA intravenous bolus given over 2 hours, followed by a 25-mg continuous infusion over the next 22 hours. Each patient was placed on a weight-based continuous heparin infusion following thrombolytic therapy.
A 72-year-old man with a medical history (PMH) of hypertension and hyperlipidemia presented to the emergency center with worsening dyspnea, fever, and chills of approximately 1 week's duration. He had been treated empirically with azithromycin on an outpatient basis for a presumed upper respiratory infection and then subsequently tested positive for COVID-19. On admission, his vital signs were temperature (T), 36.7°C; heart rate (HR), 91 bpm; respiratory rate (RR), 28; blood pressure (BP), 120/78 mm Hg. He was started on a hydroxychloroquine regimen. A chest X-ray showed minimal indistinct bibasilar opacities. The initial arterial blood gas (ABG) was significant for an arterial partial pressure of oxygen (Pao2) of 53 mm Hg and peripheral capillary oxygen saturation (SpO2) 88% on room air. There was minimal improvement with administration of supplemental oxygen by nasal cannula, and the patient was placed on a 50% venturi mask. On hospital day 2, the patient demonstrated increased work of breathing with oxygen saturations in the low 80s, so he was transitioned to high-flow nasal cannula (HFNC) 60%/40 L/min. Over the next few days, he failed to improve and had increasing oxygen requirements up to 100%/60 L/min to maintain SpO2 in the low 90s. With increasing dyspnea and fatigue, and SpO2 in the mid 80s despite maximal support by HFNC, the decision was made to intubate on hospital day 8. Two days later, the patient's oxygenation had not improved despite maximum ventilator support with airway pressure release ventilation, proning, and paralytics. He had a Pao2/FIO2 (P/F) ratio ranging from 51–72. Due to his age, he was not eligible for extracorporeal membrane oxygenation, and the decision to pursue tPA therapy was made. His pretreatment D-dimer and fibrinogen were 2.16 μg/mL and 654 mg/dL, respectively. Approximately 24 hours following tPA infusion, his P/F ratio increased to 76 from the pretreatment 69, and his oxygenation requirements decreased to an FIO2 of 80% (Fig. 1). He had an expected initial increase in D-dimer to 9.57 μg/mL (Fig. 2). His P/F ratio continued to increase daily with decreasing oxygen requirements and by posttreatment day 5 reached 121, a 175% increase from pretreatment values. His D-dimer decreased to 1.99 μg/mL. Ventilation was then deescalated from airway pressure release ventilation to pressure controlled ventilation-volume guarantee and paralytics were discontinued. By posttreatment day 8, pressure requirements were further decreased to 18 and his P/F ratio increased to 127. By posttreatment day 12, the patient successfully passed a CPAP trial and on the following day was able to be extubated to HFNC. He was subsequently transitioned to the floor on oxygen via nasal cannula.
A 68-year-old woman with PMH of hypertension, hyperlipidemia, cerebrovascular accident with residual hemiparesis, and dementia presented to the emergency center from a skilled nursing facility with worsening dyspnea and altered mental status. She was recently diagnosed with urosepsis and a right lower lobe pneumonia. She had a COVID-19–positive contact. On admission, her vitals were T, 38.2°C; HR, 124 bpm; RR, 32; BP, 98/72 mm Hg; and SpO2, 82% on room air. A chest X-ray showed an ill-defined infiltrate in the right lower lobe, and she was started on empiric piperacillin-tazobactam. She initially was placed on 100% nonrebreather (NRB) to maintain a SpO2 of 90% to 92%. She was transferred to the intensive care unit (ICU) for further management and required HFNC 60%/30 L/min to maintain oxygenation. By hospital day 3, COVID-19 testing returned positive and a repeat chest x-ray showed worsening bibasilar infiltrates. Her oxygen supplementation had increased to 100%/70 L/min, and her Pao2 was 71 mm Hg. D-dimer and fibrinogen were elevated at 1.87 μg/mL and 512 mg/dL, respectively. The decision was made to initiate tPA therapy. Approximately 2 hours after tPA bolus, the patient's SpO2 increased from 71% to 89%. Twenty-four hours later, she was placed on a heparin drip and successfully weaned from the pretreatment HFNC 100%/70 L/min to 45%/40 L/min. Her D-dimer initially increased to 5.57 μg/mL, and her fibrinogen decreased to 475 mg/dL. On posttreatment day 2, the patient unfortunately had an episode of emesis with aspiration, and the FIO2 had to be increased to 100%/50 L/min. However, the following day after this brief escalation of treatment, the patient's oxygen requirement decreased back down to 70%/50 L, and she was more engaging with the staff and able to Skype with family. At this point, she was maintaining a SpO2 in the high 80s and her D-dimer had decreased to 2.39 μg/mL (Fig. 2). Subsequently, she had a chest x-ray that showed increasing right lung infiltrate compatible with aspiration pneumonia and decompensated from a respiratory standpoint despite showing initial improvement with tPA prior to aspiration.
A 55-year-old woman with a PMH of asthma, hypertension, hyperlipidemia, and type II diabetes mellitus presented with worsening fever, cough, dyspnea, and weakness for approximately 2.5 weeks. She was previously treated with azithromycin, amoxicillin-clavulanate, and levofloxacin from her PCP and presented to our emergency center from home. Her vitals on admission were T, 39.4°C; HR, 111 bpm; BP, 115/73 mm Hg; RR, 27; with a SpO2 of 92% and Pao2 of 51 mm Hg on room air. A chest x-ray showed bilateral patchy infiltrates throughout both lungs. She was placed on supplemental oxygen by a nasal cannula and admitted to the floor for observation. On hospital day 4, she became tachypneic and her dyspnea worsened. She was subsequently placed on a NRB 100% with minimal improvement; her Pao2 was 67 mm Hg. She was transferred ICU with concern for impending intubation. COVID-19 testing returned positive. On hospital day 5, she had an elevated D-dimer of 8.34 μg/mL and fibrinogen of 899 mg/dL. The following day her Pao2 had decreased to 59 mm Hg despite being on the NRB, and the decision was made to initiate tPA therapy. On posttreatment day 1, her Pao2 improved to 72 mm Hg, her D-dimer increased to greater than 20 μg/mL, and her fibrinogen decreased to 535 mg/dL. She remained on NRB 100%. On posttreatment day 2, she completed the hydroxychloroquine regimen and was started on 80 mg methylprednisolone every 24 hours. She began further tolerating movement and was interacting with the staff, and her Pao2 further increased to 77 mm Hg. Her D-dimer stayed above 20 μg/mL. On posttreatment day 3, she was transitioned from NRBM to 6 L nasal cannula. Her D-dimer decreased to 4.56 μg/mL (Fig. 2). Posttreatment day 6, she was transferred from the ICU to the floor, and the heparin drip was discontinued, D-dimer at this point was 1.91 μg/mL. She felt well with no new complaints and was able to be weaned to room air. By posttreatment day 8, the patient no longer endorsed dyspnea and was discharged home on a steroid taper.
A 78-year-old woman with PMH of type II diabetes mellitus, hypertension, congestive heart failure, chronic kidney disease, cerebrovascular accident, prior tracheostomy for respiratory failure (since decannulated), and dementia presented to the emergency center from a skilled nursing facility with dyspnea and fever. She had a positive test for COVID-19. Her vitals on admission were T, 37.6°C; HR, 113 bpm; RR, 21; and BP, 133/66 mm Hg. A chest x-ray showed bilateral interstitial infiltrates. An initial ABG was significant for Pao2 of 48 mm Hg and SpO2 of 85% despite a 5-L oxygen supplementation by nasal cannula, and she was subsequently placed on a NRB 100%/15 L/min. By hospital day 3, her oxygen requirements increased, and she was placed on HFNC 100%/70 L/min; however, she remained hypoxemic with Pao2 of 60 mm Hg and was transferred to the ICU. A repeat chest x-ray showed increased bilateral interstitial and alveolar opacities. Her D-dimer and fibrinogen were 2.47 μg/mL and 744 mg/dL, respectively. Despite maximum HFNC therapy, she had a Pao2 of 61 mm Hg, and tPA was initiated. During the tPA administration, her Pao2 continued to decline, and the decision was made to intubate. She was sedated and placed in pressure-controlled ventilation-volume guarantee with a FIO2 of 100% and PEEP of 15 cm H2O. With mechanical ventilation, her Pao2 increased to 240 mm Hg. Over the next 24 hours, she responded remarkably well, and her FIO2 requirement was decreased from 100% to 45%. Her P/F ratios ranged from 175 to 196. Her D-dimer increased to 7.05 μg/mL and her fibrinogen decreased to 596 mg/dL. By posttreatment day 2, she maintained P/F ratios in the 190 s, her PEEP decreased from 15 cm H2O to 9 cm H2O, and she no longer required vasopressors. Significantly, she previously required a tracheostomy due to her inability to wean from the ventilator; however, she was extubated after only 2 days on the ventilator to noninvasive oxygen and was transitioned to the floor by posttreatment day 7.
An 82-year-old woman with a PMH of hypertension, hyperlipidemia, and renal insufficiency presented to the emergency center from home with a nonproductive cough of 2 weeks duration and dyspnea on exertion. At presentation, her vital signs were T, 38°C; HR, 117 bpm; RR, 28; and BP, 137/88 mm Hg. According to paramedics, she was found in respiratory distress in the field with a SpO2 in the 60s that minimally improved with supplemental oxygen. Initial ABG was significant for Pao2 of 55 mm Hg and a SpO2 of 92% despite 6 L oxygen by nasal cannula. She was then placed on NRB 100%. A chest x-ray showed bilateral mixed interstitial and alveolar changes. On hospital day 2, she had worsening dyspnea with SpO2 in the 70s on NRB 100% and a Pao2 of 57 mm Hg. She was transferred to the ICU and her COVID-19 test returned positive. She was placed on HFNC 100%/50 L/min which improved her Pao2 to 67 mm Hg. Her D-dimer and fibrinogen were 4.78 μg/mL and 753 mg/dL respectively, and the decision to pursue tPA therapy was made. Approximately 12 hours postbolus, she showed subjective improvement, denying dyspnea and stating that she was ready to go home. However, she still required HFNC 100%/50 L/min. Approximately 18 hours posttreatment, she suffered an acute desaturation episode demonstrating a Pao2 of 57 mm Hg and SpO2 of 44%. The patient had previously denied intubation, so she was transitioned to BiPAP with a FIO2 of 100% and PEEP of 10 cm H2O in a negative pressure room. She responded well and her Pao2 increased to 79 mm Hg. Her posttreatment D-dimer had increased to >20 μg/mL and her fibrinogen had decreased to 693 mg/dL. By posttreatment day 2, her D-dimer decreased to 14.06 μg/mL (Fig. 2), she was able to be weaned off of BiPAP to HFNC 100% 60 L/min without further escalation and has continued to slowly improve.
We report five cases of nontraditional, or off-label use of tPA for the treatment COVID-19 patients requiring ICU admission for hypoxia. To the author's knowledge, this is the first report of tPA delivery in nonventilated patients. None of our patients had any adverse side effects, bleeding or observed complications related to thrombolytic therapy or anticoagulation.
Over this case series of tPA delivery, we observed several clinical trends. All of our patients demonstrated an initial increase in Pao2 immediately after the initial tPA bolus. However, this increase was consistently followed by a slight, downward trend in Pao2 during the next 24 hours across all patients. A similar finding was reported by Wang et al.19 Additionally, we observed that the downward Pao2 trend after the initial improvement was not back to the patients pretreatment baseline levels, rather, settling in a more survivable Pao2 range. Confounding the interpretation of the Pao2 trend is the finding that during the treatment time period, several patients had their supplemental oxygen delivery weaned while maintaining oxygen saturations with an absence of subjective complaints such as shortness of breath or work of breathing. Ultimately, after treatment, the patients in this series were able to tolerate supplemental oxygen deescalation while maintaining a stable Pao2; whereas prior to treatment, oxygen requirements were increasing.
We also observed that each patient had an initial D-dimer of greater than 1.5 μg/mL with a range of 1.87 μg/mL to 8.34 μg/mL at time of tPA administration. During the first 24 hours posttreatment, each patient's D-dimer increased, with two patient's reaching a D-dimer of greater than 20 μg/mL. We theorize that this is reflective of active thrombolysis during tPA infusion. D-dimer levels were then noted to down trend after initiation of the heparin drip and ultimately returned toward normal values and corresponded with reduced supplemental oxygen requirements (Fig. 2).
This study's limitations include that it is an observational case series with no controls. Although the patients were treated in the same hospital and ICUs they did receive varying medications including antibiotics and medications that are of unknown clinical significance. The timing of the medication was also given during different clinical periods for each patient; however, we believe this is important to determining optimal timing for administration.
The evidence supporting the notion that COVID-19 patients are subject to a prothrombotic state is mounting. The severe hypoxia and ARDS-like picture that these patients demonstrate, coupled with refractoriness to traditional pulmonary supportive measures, adds credence to the theory that microvascular thrombosis may play a role in the gas exchange difficulties that these patients demonstrate. To the authors' knowledge, we report the largest series of tPA applications in this patient population and the only report of tPA use in nonventilated patients.
In this case series, the administration of tPA to severely hypoxic, COVID-19 patients seems to be associated with improvements in Pao2 from pretreatment values. While the Pao2 did down trend after the initial bolus, we observed that Pao2 settled in a more survivable range for all patients with an eventual increase in Pao2 seen over time. While tPA cannot be solely credited with our patients clinical improvements, we theorize that tPA administration may have improved this patient population's ability to oxygenate from Pao2 values generally considered prognostically poor to a more survivable range. We question if this augmentation of gas exchange capacity allows for the patient to better tolerate the inflammatory response mounted in defense of COVID-19 and acknowledge that more clinical investigation will be needed to validate the agent's use. In the effort to liberate patients from the need for mechanical ventilation, early application of tPA in the respiratory deteriorating COVID-19 patient may be beneficial. Additionally, consideration of increasing the bolus dose, or the infusion dose, of tPA deserves evaluation if more formal studies are to be conducted.
D.B.C. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has also participated in the writing and revising of this submission. He has reviewed the final draft of the article and approved its submission for publication. He will serve as the corresponding author. H.M.N. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. She has also participated in the writing and revising of this submission. She has reviewed the final draft of the article and approved its submission for publication. A.M.S. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has also participated in the writing and revising of this submission. He has reviewed the final draft of the article and approved its submission for publication. J.T.B. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. C.M.F. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. A.A. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. M.S.K. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. C.W.C. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. E.A.J. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. A.B.C. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has reviewed the final draft of the article and approved its submission for publication. D.W.A. has made substantial contributions to the concept and design of this project and has further participated in the analysis and interpretation of the data. He has also participated in the writing and revising of this submission. He has reviewed the final draft of the article and approved its submission for publication.
The authors declare no funding or conflicts of interest.
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