Efficacy and safety of thrombolysis in COVID19 related ARDS.

INTRODUCTION: COVID19 causes significant pulmonary microthrombi in some individuals, which can lead to ARDS and death. Thrombolysis could be an effective approach in some patients with severe ARDS. We describe our experience with usage of thrombolytic agents in COVID19 critically ill patients, who were in worsening respiratory failure. METHODOLOGY: Retrospective chart analysis was done in patients who were thrombolysed between May 2020- Sept 2020. Analysis was done to find out factors associated with improvement in oxygenation and survival. RESULTS: Twenty seven patients with severe ARDS [all had respiratory rate >30, FiO2 >0.6(on NIV/HFNC) and PiO2/FiO2 ratio<120] were thrombolysed in our ICU for COVID19 causes. C.T. Pulmonary Angiography could not be done in any of the 27 patients due to poor general condition, but 2D echo was normal in most (5 had dilated RA,RV) and none of the patients was in shock. So there was no conventional indication of thrombolysis in these patients, yet after thrombolysis, we saw dramatic changes in oxygenation (defined by decrease in FiO2 by ≥0.2) in twenty patients. Five patients had major bleed. Eleven patients survived (survival rate of 40.7%) and survival rate was high { 66% (8/12)} in patients who were thrombolysed within 2 days of oxygen requirement. CONCLUSION: In this unprecedented pandemic with high mortality rates, efficacy of early thrombolysis needs to be further explored in randomised controlled trials.

Intrapleural Tissue Plasminogen Activator and Dornase Alfa Administration for a Multiloculated Recurrent Malignant Pleural Effusion: A Case Report.

Malignant pleural effusions (MPEs) can often be very difficult to manage despite conservative interventions including thoracentesis and indwelling pleural catheter placement. These effusions can be septated and loculated, leading to complexities in drainage and symptomatic relief for patients. As such, physicians have experimented with the use of tissue plasminogen activator (t-PA) and dornase alfa (DNase) in attempts to drain complex malignant pleural effusions. Although the use of t-PA and DNase has been well studied in the context of empyema, the literature is limited in regards to the use of these medications in MPEs. Here, we present the case of a patient with a history of metastatic lung adenocarcinoma complicated by recurrent MPEs. Bedside ultrasonography revealed a septated fluid pocket in the pleural space of the right hemithorax. An indwelling pleural catheter (IPC) was placed with minimal symptomatic relief. The decision was made to administer t-PA and DNase through the IPC, resulting in the resolution of symptoms and radiographic findings. This case highlights the potential benefit of using t-PA and DNase to help drain complex malignant pleural effusions.

Acute Ischemic Stroke in Children - Should We Thrombolyze?

Ischemic stroke is a major cause of acute neurological symptoms in children with significant long-term neurological sequelae. Unlike in the adult population, the clinical presentation of strokes in children may not be stereotyped. Hence, many other differential diagnostic possibilities might have to be considered in the emergency setting. Due to this heterogeneous presentation and the resultant clinical dilemma in the early detection, acute thrombolysis even now remains as a very rarely tried therapeutic option in children. Many case reports over these years have shown consistently good results of acute intravenous thrombolysis in children with tissue plasminogen activator (tPA) administered within the time frame. There are also some recent reports of endovascular interventions. However, unlike in the adult population, class 1 clinical studies and good Randomized controlled trials (RCT) are yet to emerge in children. The absence of age-appropriate safety and outcome data for the commonly used thrombolytic agents in children is another major roadblock for developing clinical guidelines and recommendations for this age group. The ambitious Thrombolysis in Pediatric Stroke (TIPS) trial had to be terminated prematurely due to poor patient enrolment. This review critically looks at the current status of the acute management of ischemic strokes in children with a specific emphasis on thrombolytic therapy. Until we have better evidence-based guidelines for this age group, it will be prudent to develop robust institutional pathways to provide this important intervention for all eligible children with acute strokes.

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS: gov.

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series.

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.

Continued Underutilization of stroke care during the COVID-19 pandemic.

OBJECTIVE: This study aims to investigate the utilization of acute ischemic stroke (AIS) services during the Corona Virus Disease 2019 (COVID-19) pandemic. Based on early observations among healthcare utilization on stroke and other healthcare services, we hypothesized that there would be a persistent significant decline in AIS patients presenting to hospitals as the pandemic has progressed for over a year. METHOD: TriNetX, a large research network, is used to collect real-time electronic medical data. Data on utilization of acute ischemic stroke service was collected for the years 2018, 2019, and 2020 for variables including overall stroke volume and the number of patients that received intravenous tissue plasminogen activator (tPA) and mechanical thrombectomy (MT). RESULT: We found a 13.2-15.4% decrease in total number of AIS patients in 2020 (n 77231) compared with the years 2018 and 2019 (n 88948 and 91270 respectively, p â€‹< â€‹0.001). In the year 2020 Stroke volume was significantly lower in Q4 comparing to Q1 (Q1 vs Q4, p â€‹< â€‹0.01, while there were no significant differences in stroke volume between Quarters 2, 3, and 4 in 2020 (Q2 vs Q3, p â€‹= â€‹0.39, Q2 vs Q4, p â€‹= â€‹0.61, Q3 vs Q4, p â€‹= â€‹0.18). The Proportion of patients receiving tPA in 2020 was significantly lower compared to prior years (5.4% in 2020 vs 6.4% in 2018 and 6.0% in 2019, p â€‹< â€‹0.01), however, the proportion of patients receiving MT was significantly higher in 2020 than in 2018 (0.024 vs 0.022, p â€‹< â€‹0.01). CONCLUSION: Despite significant alteration in practices to optimize healthcare delivery and mitigate the collateral impact of the pandemic on care for other conditions, a persistent decline in AIS volumes remains. Delayed presentation, fear-of-contagion, reallocation, and poor availability of health care resources are potential contributors. Prospective evaluation and further investigation for these trends is needed.

Management and Prevention of Cerebrovascular Accidents in SARS-CoV-2-Positive Patients Recovering from COVID-19: a Case Report and Review of Literature.

We discuss the current understanding of COVID-19's neurological implications, their basis, and the evolving clinical consensus with a focus on cerebrovascular stroke. We further illustrate the potential significance of these implications with the aid of an accompanying case report outlining the disease course and treatment of a COVID-19 patient suffering from ischemic stroke and pulmonary embolism. The ever-growing strain on the global healthcare system due to the spread of the novel coronavirus SARS-CoV-2 requires focused attention on urgent care of independent, coexisting, and associated comorbidities, including cerebrovascular accidents. For illustration purposes, we outline the case of a 68-year-old female presenting with COVID-19 subsequently complicated by bilateral pulmonary embolism and a right-sided cerebrovascular accident. The patient was successfully managed pharmacologically and discharged without significant neurological deficit. The evidence for a hypercoagulable state in this patient along with discussion of mechanistic bases, corroborative evidence from the literature, along with relevant guidance on screening, treatment, and prophylaxis is offered. Greater study of the pathogenesis of COVID-19-related cerebrovascular complications and revisiting current guidelines on their management including potentially heightened levels of thromboprophylaxis are warranted.

Successful use of tPA for thrombolysis in COVID related ARDS: a case series.

We describe successful usage of low dose Tissue plasminogen activator (tPA) (30-50 mg) in three COVID19 critically ill patients, who were in worsening respiratory failure in-spite of being on therapeutic anticoagulation. All patients had respiratory rate > 40; FiO2 > 0.7(on NIV); PiO2/FiO2 ratio < 100 and D-dimer>1000 ng/ml. C.T. Pulmonary Angiography could not be done in these patients due to poor general condition, but 2D echo was normal and none of the patients was in shock. So there was no conventional indication of thrombolysis in these patients, yet after thrombolysis, we saw dramatic changes in oxygenation. All patients became off oxygen within 3-7 days and were discharged within 2 weeks. The whole idea was to prevent intubation, since mortality rates are very high in intubated COVID19 patients. tPA is associated with <1% risk of fatal bleed. In this unprecedented pandemic with high mortality rates, thrombolysis could be an effective and safe option in carefully selected critically ill patients of COVID19.

Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis.

BACKGROUND: COVID-19 threatens to quickly overwhelm our existing critical care infrastructure in the USA. Systemic tissue plasminogen activator (tPA) has been previously demonstrated to improve PaO2/FiO2 (mmHg) when given to critically ill patients with acute respiratory distress syndrome (ARDS). It is unclear to what extent tPA may impact population-based survival during the current US COVID-19 pandemic. METHODS: A decision analytic Markov state transition model was created to simulate the life critically ill COVID-19 patients as they transitioned to either recovery or death. Two patient groups were simulated (50,000 patients in each group); (1) Patients received tPA immediately upon diagnosis of ARDS and (2) patients received standard therapy for ARDS. Base case critically ill COVID-19 patients were defined as having a refractory PaO2/FiO2 of < 60 mmHg (salvage use criteria). Transition from severe to moderate to mild ARDS, recovery, and death were estimated. Markov model parameters were extracted from existing ARDS/COVID-19 literature. RESULTS: The use of tPA was associated with reduced mortality (47.6% [tTPA] vs. 71.0% [no tPA]) for base case patients. When extrapolated to the projected COVID-19 eligible for salvage use tPA in the USA, peak mortality (deaths/100,000 patients) was reduced for both optimal social distancing (70.5 [tPA] vs. 75.0 [no tPA]) and no social distancing (158.7 [tPA] vs. 168.8 [no tPA]) scenarios. CONCLUSIONS: Salvage use of tPA may improve recovery of ARDS patients, thereby reducing COVID-19-related mortality and ensuring sufficient resources to manage this pandemic.