Using lysis therapy to treat five critically ill COVID‐19 patients who show echocardiographic criteria of right ventricular strain

Abstract New options for treatment escalation in critically ill COVID‐19 patients are unmet need. Five critically ill patients were treated using a low‐dose protocol thrombolytic therapy in the form of intravenous alteplase infusion over 15 min (0.6 mg/kg). This therapeutic intervention yielded an immediate favorable outcome on follow up and all five patients were extubated and transferred to the ward. This report suggests that bedside echocardiography can be a beneficial tool in the urgent assessment of the right ventricle—to—pulmonary vascular coupling in mechanically ventilated COVID‐19 patients, and thrombolytic therapy may be beneficial in hemodynamically unstable patients who show echocardiographic criteria of right ventricular strain.


INTRODUCTION
The case-fatality rate of COVID-19 patients characterized clinically as mild is 0%, while it reaches 50% in those patients who are clinically characterized as critical [1,2]. These numbers indicate a critical point in the pathogenesis of COVID-19 against which the current therapeutic approach proves to be ineffective. Over the past several months, our understanding of the disease has been changed by multiple landmark achievements that highlight the role of COVID-induced hypercoagulability in patients' outcomes [3][4][5][6]. Coagulopathy associated with COVID-19 may be driven by the production of prothrombotic autoantibodies [7] in addition to microthrombogenic responses that occur when endothelial insult takes place [8]. This reaction is aggravated causing enhanced platelet activation [9], and the microthrombotic pathway is maintained by the activation of both the coagulation factors and the endothelium [6]. Therefore, in situ immune-thrombosis plays a significant role as a primary mechanism explaining the micro-and macrothrombotic manifestations of the disease [10]. *Tocilizumab was received as a single IV dose of 8 mg/kg (max 800 mg) within 3 days of hospitalization. **Anticoagulation therapy was administered in a prophylactic dose. ***All patients continued to receive oxygen therapy at the ward, and Patient 5 was discharged from the hospital on home oxygen.

Patients
COVID-19 patients were eligible to receive lysis therapy if they fulfilled the following criteria: (i) had a rapidly progressive severe pneumonia, (ii) were currently supported by mechanical ventilation, (iii) PaO 2 /FiO 2 ratio < 300 (wherein PaO 2 measured in mmHg and FiO 2 is the fraction of inspired oxygen expressed as a decimal), and (iv) the echocardiographic examination showed one or more criterion of right ventricular strain.

Lysis therapy
A low-dose protocol of recombinant tissue-type plasminogen activator [14] was implemented, wherein Alteplase (Activase®, Genentech) was intravenously infused over 15 min with a dose of 0.6 mg/kg (the maximum dose is 50 mg) [15].

RESULTS
Five patients (age range, 40-83 years; 1 woman) were treated with lysis therapy. None of whom was a smoker, and three patients had preexisting medical conditions in the form of diabetes mellitus, hypertension, and ischemic cardiomyopathy. All five patients had received tocilizumab (within 3 days of hospitalization) and low-dose steroids without antiviral treatments ( Table 1).
All five patients were mechanically ventilated at the time of lysis therapy administration, all of them were weaned from mechanical ventilation and extubated postlysis (Table 1). Patient 5 was receiving ECMO at the time of lysis therapy administration but did not require ECMO within 6 days postlysis. All patients were transferred to the ward and eventually discharged from the hospital; length of stay was 40, 62, 25, 50, and 58 days, respectively (Patient 5 discharged on home oxygen due to pulmonary fibrosis).

Change in hemodynamics
At the time of lysis therapy administration, all patients were hemodynamically unstable on circulatory support in the form of norepinephrine plus or minus vasopressin. The resultant mean arterial blood pressure (MAP) ranged from 60 to 70 mmHg. Upon administration of lysis therapy, all patients were gradually weaned from the circulatory support, and the MAP gradually increased over 80 mmHg within a time period that ranged from 7 to 12 days (Table 2, Figure 1A).

Change in SOFA score
The SOFA score ranged from +6 to +10 prior to receiving lysis therapy and decreased to a range of +1 to +5 at the twelfth day (the seventh day for Patient 1) following administration of lysis therapy (Table 2 and Figure 1C). The SOFA score is calculated using six systems: respiratory, coagulation, hepatic, cardiovascular, central nervous system, and kidney; and the worst value on each day was recorded.

Change in laboratory markers and body temperature
All five patients had high-sensitivity cardiac troponin levels that ranged  Figure 1D).   MAP, mean arterial pressure; P/F ratio, PaO 2 /FiO 2 ratio; SOFA score, sequential organ failure assessment score.

Safety and adverse effects
The implemented low-dose protocol of alteplase seems to be effective and well tolerated. All five patients did not suffer significant side effects or bleeding.

DISCUSSION
In this report, thrombolytic therapy was used to treat five hemody-

Recommendations
The main recommendations of this report are the following:

Limitations
This study has following limitations: (i) a case series included no controls and (ii) alteplase was administered immediately after fulfilling the patient inclusion criteria; whether a different timing of administration would have been associated with different outcomes cannot be determined.

CONCLUSION
In this case-series of five mechanically ventilated, hemodynamically