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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 12
| Issue : 4 | Page : 197-203 |
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Systemic Thrombolytics as Rescue Therapy for COVID-19 Patients With Acute Respiratory Distress Syndrome: A Retrospective Observational Study
Prathibha Gowda Ashwathappa, Ipe Jacob, Pradeep Rangappa, Karthik Rao
Department of Critical Care, Manipal Hospital, Bengaluru, Karnataka, India
| Date of Submission | 18-Jun-2022 |
| Date of Acceptance | 04-Aug-2022 |
| Date of Web Publication | 26-Dec-2022 |
Correspondence Address:
Dr. Ipe Jacob
Department of Critical Care, Manipal Hospital, Yeshwantpur, Bengaluru, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijciis.ijciis_45_22
 Abstract | | |
Background: Coronavirus disease 2019 (COVID-19) pneumonia with severe acute respiratory distress syndrome (ARDS) is often associated with a progressive respiratory failure that is refractory to maximal ventilatory support and other ARDS strategies. Studies show evidence of a hypercoagulable state in COVID-19 patients, including capillary thrombosis and alveolar fibrin deposits which impede normal gas exchange. In this context, thrombolysis is considered as a salvage therapy to rescue critically hypoxemic patients.
Methods: In this retrospective observational study, the efficacy of thrombolysis on outcome of COVID-19 ARDS with respiratory failure was analyzed. Patients with severe ARDS and d-dimer levels of 5 μg/ml or above were initiated on alteplase, as a 25 mg bolus followed by a 25 mg infusion over 22 h. Primary outcome was intensive care unit (ICU) mortality and secondary outcomes were change in PaO2/FiO2 24 h after thrombolysis, avoidance of intubation, ventilator free days (VFD), and ICU and hospital length-of-stay (LOS).
Results: Thirteen out of 34 patients with severe COVID ARDS underwent thrombolysis. They had lower ICU mortality than non-thrombolysed patients (23.1% vs. 71.4%, P = 0.006), greater percentage improvement in PaO2/FiO2 (116% vs. 31.5%, P = 0.002), more VFDs (13 days vs. 0 day, P = 0.004), and lesser requirement for intubation (23.1% vs. 76.2%, P = 0.004). ICU and hospital LOS were similar.
Conclusion: Thrombolysis can be considered as a rescue therapy for nonintubated COVID-19 ARDS patients with severe hypoxemic respiratory failure, who show evidence of a procoagulant state. Larger studies are needed before inclusion into the regular treatment protocol for COVID-19 patients.
Keywords: Acute respiratory distress syndrome, coronavirus disease 2019, d-dimer test, respiratory failure, thrombolytic therapy
How to cite this article:
Ashwathappa PG, Jacob I, Rangappa P, Rao K. Systemic Thrombolytics as Rescue Therapy for COVID-19 Patients With Acute Respiratory Distress Syndrome: A Retrospective Observational Study. Int J Crit Illn Inj Sci 2022;12:197-203 |
How to cite this URL:
Ashwathappa PG, Jacob I, Rangappa P, Rao K. Systemic Thrombolytics as Rescue Therapy for COVID-19 Patients With Acute Respiratory Distress Syndrome: A Retrospective Observational Study. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Mar 30];12:197-203. Available from: https://www.ijciis.org/text.asp?2022/12/4/197/364743 |
| Introduction | |  |
Coronavirus disease 2019 (COVID-19) pneumonia with acute respiratory distress syndrome (ARDS) is associated with a high mortality of 22%–64%.[1] This is attributed to progressive respiratory failure resulting from widespread thrombotic microangiopathy in pulmonary vessels, as well as intra-alveolar fibrin deposits, which may impair normal gas exchange.[2] Capillary microthrombi have been found to be nine times more common in COVID-19 lungs than in H1N1.[3] Many autopsy studies have shown a procoagulant state in COVID-19 pneumonia, with common findings being intra-alveolar deposition of fibrin, microthrombi in alveolar capillaries, and platelet–fibrin thrombi in small arterioles (<1 mm diameter), with near-total or complete occlusion of these vessels.[3],[4],[5],[6] Thromboelastography (TEG) studies also show a hypercoagulable and hypofibrinolytic state in COVID-19 patients, accompanied by high serum d-dimer levels.[7],[8],[9],[10] This is corroborated by radiological evidence of thrombosis, mainly an increased incidence of pulmonary emboli and deep vein thrombosis, perfusion defects on dual-energy computed tomography (DECT), as well as clinical signs such as increased clot formation in renal replacement circuits and extracorporeal membrane oxygenation circuits, despite being on therapeutic anticoagulation.[2],[11],[12],[13]
Anticoagulants and fibrinolytics have targeted this imbalance between coagulation and fibrinolysis.[14],[15],[16] A meta-analysis on acute lung injury showed that fibrinolytics improved oxygenation and mortality,[17] similar to another study in which twenty patients with severe ARDS were treated with intravenous (IV) urokinase.[18] Pulmonary microthrombi may lead to increased dead space ventilation, which is reversed with thrombolysis.[19] In this background, Barrett et al. suggested the use of tissue plasminogen activator (tPA) in COVID-19 ARDS patients with persistent, refractory hypoxemic respiratory failure.[1]
The Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19 (STARS), a large randomized controlled trial (RCT) on thrombolysis in COVID-19 ARDS, showed that the combination of a tPA bolus plus heparin improved oxygenation, although ventilator-free days (VFD) and mortality remained unchanged.[20] Other experiences with thrombolysis include a few case series which showed clinical improvement postthrombolysis.[21],[22],[23],[24],[25],[26],[27] None of them, however, had incorporated controls for comparison and therefore causation and efficacy could not be attributed to thrombolysis with certainty.
| Methods | | |
Study design and aim
This was a retrospective observational study of adult patients admitted to a tertiary care intensive care unit (ICU) with a diagnosis of COVID-19 pneumonia with severe ARDS, over a 1-year period between April 1, 2020, and March 31, 2021. The study aimed to ascertain the benefit of thrombolysis in improving clinical outcome in patients who had evidence of a procoagulant state. It was approved by the institutional ethics committee and registered at Clinical Trials Registry-India (CTRI) (registration number CTRI/2021/08/035445; registration date: December 30, 2020).
Outcome measures
The primary outcome was ICU mortality and the secondary outcomes were change in PaO2/FiO2 at 24 h after thrombolysis, VFD, avoidance of intubation, ICU length of stay (LOS), and hospital LOS. VFD was defined as days free from both invasive and noninvasive ventilation, including home bilevel positive airway pressure (BiPAP) machines.[28]
Study population
The inclusion criteria were adult patients with SARS-COV-2 pneumonia proven by reverse transcription–polymerase chain reaction or rapid antigen test, on noninvasive positive pressure ventilation (NIPPV), requiring FiO2 of 100% and a minimum positive end expiratory pressure (PEEP) of 5 cm, with PaO2/FiO2 ratios below 100 and serum d-dimer levels 10 times or more than the normal upper limit of 0.5 μg/ml. The study population was divided into a thrombolysis group who underwent intervention with alteplase, and the nonthrombolysis (control) group.
Treatment and intervention
All patients received a uniform SARS-CoV-2 pneumonia protocol-based treatment including IV remdesivir 100 mg once daily (OD), IV methylprednisolone 60 mg as infusion over 24 h, tablet aspirin 75 mg OD, IV ranitidine 50 mg thrice daily, and a therapeutic dose of subcutaneous low-molecular-weight heparin (LMWH) 1 mg/kg twice daily. Study participants with no contraindications to thrombolysis [Table 1] were started on alteplase as a 25 mg bolus followed by an infusion of 25 mg over 22 h, with monitoring for overt bleeding, altered sensorium, or hemodynamic instability. LMWH was withheld for 12 h before and during thrombolysis and restarted immediately afterwards.
Statistical analysis
Data were collected from patient charts and electronic medical records (Care 21© Hospital Information Management Systems Software, Columbia Asia, India) using International Classification of Diseases-10 codes and analyzed using Predictive Analytics SoftWare Statistics for Windows, Version 18.0, IBM, Chicago, Illinois, USA, released 2009. Normality of data was tested using Shapiro test. Mann–Whitney U-test was used to compare actual and percentage change in PaO2/FiO2, ICU-LOS, and hospital LOS between thrombolysis and nonthrombolysis groups. Fisher's exact test was used to compare intubation rates between the two groups. Wilcoxon signed-rank test was used to compare pre- and postthrombolysis PaO2/FiO2. P < 0.05 was considered statistically significant.
| Results | | |
Thirty-four patients met the inclusion criteria, of whom thirteen underwent thrombolysis. Of the remainder, twelve patients did not consent to thrombolysis, three were above 80 years, four had severe uncontrolled hypertension, one had a previous intracranial hemorrhage, and one developed epistaxis 2 days after admission. These 21 patients formed the nonthrombolysis control group. A 2-D echocardiogram was done prior to thrombolysis to rule out myocardial dysfunction. All patients had normal ventricular function with Doppler study showing normal pulmonary arteries, mild-to-moderate tricuspid regurgitation, and pulmonary artery systolic pressure ranging from 25 to 45 mm Hg.
The results of this study are shown in [Table 2] and [Table 3]. Patients in the thrombolysis group ranged from 45 to 66 years of age, with a mean age of 56 years (standard deviation [SD] = 12.46), while those in the nonthrombolysis group ranged from 29 to 84 years of age, with a mean age of 65 years (SD = 7.52). Males constituted 85% of both groups. The Charlson Comorbidity Index (CCI) score was lower in the thrombolysis group than in the nonthrombolysis group (median 1 [interquartile range [IQR] 1.0–3.0] vs. 3 [IQR 2.0–4.8], P = 0.004). However, both the groups had similar mean APACHE II scores (median 10.0 [IQR 8.0–12] in the thrombolysis group vs. 11.0 [IQR 8.8–15.5] in the nonthrombolysis group, P = 0.145). The interval from ICU admission to thrombolysis ranged from 4 to 10 days. | Table 2: Comparison of outcomes between the thrombolysis and nonthrombolysis groups
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 | Table 3: Change in PaO2/FiO2 within the thrombolysis group and nonthrombolysis groups
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Mortality in the thrombolysis group was 23.1% versus 71.4% in the nonthrombolysis group (P = 0.006). PaO2/FiO2 ratios were equivalent between the two groups prior to thrombolysis (median 81.0 [IQR 66.0–90.5] vs. 70.0 [IQR 64.0–80.0], P = 0.227). Twenty-four hours postthrombolysis, thrombolysed patients showed an improvement in PaO2/FiO2 compared with their prethrombolysis values (162.0 [IQR 101.0–253.0] vs. 81.0 [IQR 66.0–90.5], P < 0.001). This improvement was also seen when compared with nonthrombolysed patients (162.0 [IQR 101.0–253.0] vs. 96.0 [IQR 80.0–115.0] P = 0.008). PaO2/FiO2 ratios were also shown to have increased in percentage terms: thrombolysed patients had a 116.0% increase in PaO2/FiO2 (IQR 76.6–179.5) as compared to 31.5% in nonthrombolysed patients ([IQR 20.8–59.5] P = 0.002). A notable finding was that nonthrombolysed patients also showed improved PaO2/FiO2, 24 h after being considered for thrombolysis (70.0 [IQR 64.0–80.0] vs. 96.0 [IQR 80.0–115.0] P < 0.001). Ten patients (76.9%) of the thrombolysis group were discharged without the need for intubation versus 6 patients (28.5%) in the nonthrombolysis group (P = 0.004). Thrombolysed patients also had more VFDs (median 13.0 days [IQR 10.0–23.5]), while nonthrombolysed patients had none (median 0 days [IQR 0–9.0]) (P = 0.004). ICU-LOS and hospital LOS did not differ between the two groups.
[Table 4] compares serum d-dimer levels among survivors and nonsurvivors in the thrombolysis and nonthrombolysis groups. Day 0 depicts the peak d-dimer levels, at which point thrombolysis was considered. Among the thrombolysed patients, survivors had a median d-dimer level of 13.4 μg/dl (IQR 10.9–25.7) on day 0, while nonsurvivors had a median d-dimer of 8.6 μg/dl (IQR 8.2–8.6) at the same time. Among the nonthrombolysed patients, median d-dimer levels were 10.4 μg/dl (IQR 7.3–14.6) and 9.8 μg/dl (IQR 7.4–27.5) among survivors and nonsurvivors, respectively. | Table 4: Comparison of change in serum d-dimer levels between the thrombolysed and nonthrombolysis groups
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Adverse events
One patient developed melena about 4 days after thrombolysis, secondary to bleeding from stress ulcers, which was conservatively managed with pantoprazole infusion. No other bleeding complications were noted during the procedure or the remainder of the hospital stay.
| Discussion | | |
This study examines the benefits of thrombolysis in COVID-19 patients with severe ARDS and evidence of a procoagulant state. In a review of the scientific rationale behind fibrinolytic therapy in COVID-19 ARDS, Barrett et al. suggested that thrombolysis should be considered only in patients with persistent, refractory hypoxemic respiratory failure despite maximal management strategies, with evidence of a hypercoagulable state and who have normal lung compliance with high alveolar–arterial oxygen gradients.[1] The dosage suggested is an IV bolus dose of 50 or 100 mg of alteplase over 2 h, concomitant with, or immediately followed by, systemic anticoagulation with heparin. The Moderate Pulmonary Embolism (PE) Treated with Thrombolysis trial found that 50 mg of alteplase was effective in treating moderate PE as well as reducing mortality, proposing that the lungs are uniquely sensitive to thrombolysis, being the only organ to receive a 100% of the cardiac output, and do not require the higher alteplase doses used in systemic thrombolysis.[29] A similar finding was seen in the Zhang meta-analysis where a 50 mg of alteplase to treat acute PE was found as effective as a standard dose of 100 mg, while there were more major bleeding events in the higher dose.[30] Wang et al.,[21] Christie et al.,[23] and Barrett et al.[26] have used a similar low-dose alteplase regimen in the treatment of severe COVID ARDS. Following this evidence, our study used a thrombolysis regimen of alteplase given as a bolus of 25 mg over 2 h followed by an infusion of 25 mg over 22 h.
The STARS Phase II trial is the first RCT that examines the benefits and safety of tPA in severe COVID-19 respiratory failure.[20] In Phase I of the study, a control group who received standard-of-care treatment was compared with an intervention group who received a 50 mg tPA IV bolus followed by 7 days of heparin to maintain an activated partial thromboplastin time (PTT) of 60–80 s. In the tPA bolus group, PaO2/FiO2 improved significantly, but the trial did not detect significant differences in VFD and in-hospital mortality.
The need to resume therapeutic anticoagulation soon after thrombolysis to prevent reocclusion of capillaries and loss of clinical improvements is evident from Phase II of the STARS trial, where the control group was compared with an intervention group who received a 50 mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h. The intervention group showed no significant improvement, suggesting that any revascularization effect of the initial tPA bolus was lost by the lack of therapeutic anticoagulation during the low-dose tPA infusion over the subsequent 24 h, probably leading to rethrombosis of the microvasculature. Parallels can be drawn from the GUSTO-I trial of myocardial infarction, which showed reinfarctions on stopping heparin.[31] In our study, therapeutic anticoagulation was withheld during the 24-h period of thrombolysis and restarted immediately afterward. Most of the patients in the case series described above received an infusion of unfractionated heparin, given at a rate of 500u/h during the alteplase bolus, followed by a higher dose targeted at PTT of 60–90 s, concurrent with the remaining alteplase infusion.
In the Barrett et al.'s study, three patients who failed to sustain the initial improvement in PaO2/FiO2 were suspected to have reocclusion of blood vessels and underwent a second round of thrombolysis, which improved outcome in two of them. The STARS trial also employed a similar strategy of a second tPA bolus in selected patients, which resulted in a second peak in the PaO2/FiO2 and sustained higher values for up to 7 days.
[Table 2] and [Table 3] show the changes in primary and secondary outcome measures. Mortality in thrombolysed patients (23%) was significantly lower than in nonthrombolysed patients (71%). Twenty-four hours postthrombolysis, PaO2/FiO2 values increased by 116% in thrombolysed patients, as compared to 32% in nonthrombolysed patients. A similar trend of a sharp improvement in PaO2/FiO2 by 50%–100% was also seen in the thrombolysis case series.[21],[22],[23],[24],[25],[26],[27]
In the present study, thrombolysed patients were also able to be weaned off NIPPV onto Hudson mask oxygen, prior to discharge from ICU. Whereas, nonthrombolysed survivors were unable to be completely weaned off NIPPV and required the support of home BiPAP to be shifted out of ICU. This translated into a median of 13 VFDs in thrombolysed patients versus nil VFD in nonthrombolysed patients. However, ICU-LOS and hospital LOS did not differ between the two groups.
Another finding was that only 23.1% of thrombolysed patients required intubation, as compared to 76.2% in the nonthrombolysis group, a benefit also seen in other studies. This is significant since mortality was 100% in patients who required intubation in our study, whether thrombolysed or not. High mortality has also been described in intubated patients in other studies of severe COVID-19 ARDS, including a large study which showed monthly mortality ranging from 40% to 50%.[32] These findings suggest a benefit in initiating thrombolytic therapy early in severe COVID-19 ARDS with evidence of a procoagulant state, especially in patients with a high likelihood of requiring intubation.
In this study, the decision to thrombolyse was based on a group of criteria including severe hypoxemia as evidenced by PaO2/FiO2 below 100, failure to improve oxygenation despite prone positioning on NIPPV with FiO2 of 100% and PEEP ranging from 8 to 14 cm water, and evidence of a prothrombotic state, indicated by d-dimer levels 5 μg/ml or higher. Similarly, all the patients in the case series had been initiated on thrombolysis as a last-resort measure when all other ARDS treatment modalities had failed, including lung-protective ventilation, prone positioning, optimal PEEP guided by esophageal manometry, inhaled nitric oxide, nebulized epoprostenol, and use of muscle relaxants. In addition to d-dimer levels, some studies used other evidence of abnormal coagulation/reduced fibrinolysis including raised fibrinogen levels and low LY30 values on TEG studies. Pulmonary hypertension and right ventricular dysfunction, assessed using transthoracic echocardiography and/or pulmonary artery catheterization, and pulmonary arterial thrombosis on computed tomography pulmonary angiography (CTPA), and perfusion defects on DECT were also used as evidence to initiate thrombolysis.[27] In this study, CTPA was done only for two patients. One had thromboembolism in lower segmental branches of bilateral interlobar pulmonary arteries extending into the subsegmental branches, while the other had acute PE in few segmental arteries of left lower lobe.
Serum d-dimer levels above the normal upper limit of 0.5 μg/ml have been considered as a universal sign of venous thrombosis as well as a marker of COVID-19 severity.[33],[34],[35] In the present study, d-dimer of more than 5 μg/ml was taken as the threshold to consider thrombolysis. The median d-dimer values at time of consideration for thrombolysis (day 0) and its trend over the next 4 days are shown in [Table 4]. The wide range of d-dimer levels is possibly due to individual variation in the degree of local fibrinolysis in alveoli by urokinase-type plasminogen activator released from alveolar macrophages.[8] This may also account for the significant improvement in PaO2/FiO2 in some patients in this study who were not thrombolysed.
In addition to the fall in d-dimer levels, other indicators of successful thrombolysis include a 50% increase in the mean LY30 values on TEG, reduction in fibrinogen levels, and improved pulmonary artery patency and enhancement on DECT.[26],[27],[36] However, successful thrombolysis remains best assessed by clinical signs such as improvement in oxygenation and a quicker weaning off NIPPV.
Thrombosis in COVID-19 has been seen to occur independent of the traditional venous thromboembolic risk factors such as old age, malignancy, venous thromboembolic disease, smoking, and obesity.[34] A study by Tang et al. showed that 78% of COVID-19 pneumonia nonsurvivors had signs of disseminated intravascular coagulation (DIC) with prolonged prothrombin time, PTT, thrombocytopenia, and raised serum d-dimer.[35] However, TEG studies show that COVID-19 induces more of a hypercoagulable state than DIC.[7],[8],[9],[10],[12] This hypercoagulability can be explained by increased levels of procoagulant factors seen in COVID-19, especially factor VIII, von Willebrand factor, and circulating microvesicles, which are known determinants of venous thromboembolism, and decreased levels of the naturally occurring anticoagulant factors such as antithrombin and protein C.
The inflammatory process seen in ARDS can itself contribute to the abnormal coagulation by triggering the release of inflammatory cytokines from lymphocytes, activated macrophages, and endothelium, including interleukin-1, interleukin-6, and tissue necrosis factor-α.[16] This so-called cytokine storm may cause further endothelial damage and the release of tissue factor. Increased tissue factor and factor VII production by alveolar epithelial cells and macrophages in response to inflammation, in addition to significantly depressed alveolar fibrinolytic activity, can account for the increased intra-alveolar deposition of fibrin.[1],[37]
A trial of thrombolytics in ARDS patients showed that both streptokinase and urokinase can significantly improve oxygenation.[18] However, tPA has an additional advantage in having an anti-inflammatory activity as well as enhanced plasminogen activation in the presence of fibrin leading to greater clot lysis.[16]
Limitations
This is a single center study with a small sample size. Furthermore, the number of patients in the intervention and control arms did not match. Nonthrombolysed patients had a higher CCI score, suggesting that their baseline health status was worse than the thrombolysed patients. However, this study presents evidence for further controlled trials with a large sample size.
| Conclusion | | |
Fibrinolytic therapy with tPA may be used as a viable option in nonintubated SARS-COV2 patients with severe, refractory ARDS, with evidence of a procoagulant status and who have failed to improve with maximal oxygen therapy and other ARDS management strategies. Although there is a strong pathophysiological basis to the use of tPA as well as improved clinical outcome as shown in this study, its efficacy and safety needs to be proven in larger clinical trials before it is can more widely recommended as part of the SARS-COV2 treatment regimen.
Research quality and ethics statement
This study was approved by the Institutional Review Board/Ethics Committee at Manipal Hospital, Yeshwantpur, Bengaluru (Approval # ECR/105/Inst/ KA/2013/RR19; Approval date November 23, 2020). The trial was registered at Clinical Trials Registry - India (Registration # CTRI/2021/08/035445; Registration date December 30, 2020). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guideline, specifically the STROBE guideline, during the conduct of this research project
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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