What information is there on the administration of inhaled alteplase in adult and pediatric patients? What are the indications?

Comment by InpharmD Researcher

Evidence assessing the use of inhaled alteplase is limited and primarily derived from case studies and small observational studies. In adults, inhaled alteplase has been investigated for COVID-19-related respiratory failure, showing potential to improve oxygenation, particularly in patients receiving non-invasive respiratory support. In pediatric patients, inhaled alteplase has been used for plastic bronchitis and to prevent airway cast formation after cardiac surgery, with reports indicating benefits in airway clearance and reduced duration of mechanical ventilation. Despite these findings, further robust data are needed to confirm the optimal dosing and indications for inhaled alteplase.

Background

A 2023 proof-of-concept safety study evaluated nebulized recombinant tissue plasminogen activator (rt-PA; alteplase) in adults with COVID-19-associated respiratory failure and a PaO₂/FiO₂ (P/F) ratio <300 mmHg who required either invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS). In Cohort 1 (C1), patients received 10 mg every 6 hours for 72 hours, but the protocol was amended after a relapse in oxygenation occurred post-treatment, prompting a shift to a flexible, endpoint-driven regimen for 5-14 days based on oxygen needs and fibrinogen levels. In Cohort 2 (C2), patients on IMV received 20 mg every 8 hours (60 mg/day), while those on NIRS received 60 mg/day for two days, followed by 40 mg/day for the remainder of the 14-day treatment period. Across both cohorts, nebulized rt-PA was generally well tolerated. Among the 35 treated patients (9 in C1, 26 in C2), four bleeds in three patients were attributed to the drug (one severe, three mild), and no significant fibrinogen reductions were observed. Regarding efficacy, patients in C1 experienced a greater mean improvement in P/F ratio compared with matched historical controls (154 to 299 vs. 154 to 212). In C2, NIRS patients showed greater improvements in P/F ratio (126 to 240) and required fewer treatment days compared with IMV patients (120 to 188; 7.86 vs. 10.5 days). These findings suggest that nebulized rt-PA may improve oxygenation, particularly in patients on non-invasive support, with minimal safety concerns. However, randomized clinical trials are needed to confirm efficacy and define clinical benefit. [1]

Numerous case studies have described the use of inhaled tissue plasminogen activator (tPA) in the management of plastic bronchitis in pediatric patients. Although cast prevention was not always the primary goal, available reports noted that treatment with inhaled tPA benefited patients when other therapies failed. Some cases also suggested that airway clearance with inhaled tPA reduced the need for prolonged mechanical ventilation and postoperative morbidity. Additionally, cases involving pediatric patients undergoing cardiac transplantation suggested that initiating empiric inhaled tPA immediately after surgery helped prevent cast formation and severe obstructive airway disease. Due to the anecdotal nature of the data, along with variations in dosages, treatment durations, and patient presentations, caution in interpretation is warranted. [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]

References:

[1] Chowdary P, Agarwal B, Peralta MR, et al. Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial. J Clin Med. 2023;12(18):5848. Published 2023 Sep 8. doi:10.3390/jcm12185848
[2] Wakeham MK, Van Bergen AH, Torero LE, Akhter J. Long-term treatment of plastic bronchitis with aerosolized tissue plasminogen activator in a Fontan patient. Pediatr Crit Care Med. 2005;6(1):76-78. doi:10.1097/01.PCC.0000149320.06424.1D
[3] Parent JJ, Darragh RK, Gossett JG, et al. Strategies to Prevent Cast Formation in Patients with Plastic Bronchitis Undergoing Heart Transplantation. Pediatr Cardiol. 2017;38(5):1077-1079. doi:10.1007/s00246-017-1568-y
[4] Do P, Randhawa I, Chin T, Parsapour K, Nussbaum E. Successful management of plastic bronchitis in a child post Fontan: case report and literature review. Lung. 2012;190(4):463-468. doi:10.1007/s00408-012-9384-x
[5] Colaneri M, Quarti A, Pozzi M, Gasparini S, Carloni I, de Benedictis FM. Management of plastic bronchitis with nebulized tissue plasminogen activator: another brick in the wall. Ital J Pediatr. 2014;40(1):18. Published 2014 Feb 13. doi:10.1186/1824-7288-40-18
[6] Lubcke NL, Nussbaum VM, Schroth M. Use of aerosolized tissue plasminogen activator in the treatment of plastic bronchitis. Ann Pharmacother. 2013;47(3):e13. doi:10.1345/aph.1R690
[7] Do TB, Chu JM, Berdjis F, Anas NG. Fontan patient with plastic bronchitis treated successfully using aerosolized tissue plasminogen activator: a case report and review of the literature. Pediatr Cardiol. 2009;30(3):352-355. doi:10.1007/s00246-008-9312-2
[8] Costello JM, Steinhorn D, McColley S, Gerber ME, Kumar SP. Treatment of plastic bronchitis in a Fontan patient with tissue plasminogen activator: a case report and review of the literature. Pediatrics. 2002;109(4):e67. doi:10.1542/peds.109.4.e67
[9] Parent JJ, Darragh RK. Severe airway obstruction from a bronchial cast after cardiac transplantation. Cardiol Young. 2014;24(4):739-740. doi:10.1017/S1047951113001066
[10] Grutter G, Di Carlo D, Gandolfo F, et al. Plastic bronchitis after extracardiac Fontan operation. Ann Thorac Surg. 2012;94(3):860-864. doi:10.1016/j.athoracsur.2012.04.043
[11] Heath L, Ling S, Racz J, et al. Prospective, longitudinal study of plastic bronchitis cast pathology and responsiveness to tissue plasminogen activator. Pediatr Cardiol. 2011;32(8):1182-1189. doi:10.1007/s00246-011-0058-x
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What information is there on the administration of inhaled alteplase in adult and pediatric patients? What are the indications?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Current Evaluation and Management of Plastic Bronchitis in the Pediatric Population

Design

Observational, retrospective, single-center study

N= 34

Objective

To review the presentation, characteristics, and management strategies used at Boston Children’s Hospital in a uniquely large set of patients with plastic bronchitis (PB) over a 20-year period

Study Groups

Study cohort (N= 34)

Inclusion Criteria

Plastic bronchitis diagnosis

Exclusion Criteria

Not described

Methods

Medical records for identified patients were reviewed for data regarding demographics, clinical presentation, diagnosis, management, and outcomes.

Duration

January 1997 to July 2017

Outcome Measures

Treatment modalities and interventions

Baseline Characteristics

  

SVHD (n= 24)

Respiratory disorders (n= 9)

Age at PB onset, years (IQR)

5.5 (9.0)

6.0 (4.4)

Male

 14 (58.3%) 5 (55.6%)

Diagnosis

Clinical presentation

Bronchoscopy findings

Pathology of casts

 

20 (83.3%)

7 (29.2%)

13 (54.2%)

 

7 (77.8%)

7 (77.8%)

3 (33.3%)

Abbreviations: IQR= interquartile range; SVHD= single ventricle heart disease

Results

Endpoint

SVHD (n= 24)

Respiratory disorders (n= 9)

Treatment modality

Bronchoscopy for cast removal

Chest physiotherapy

Albuterol

Inhaled steroids

Nebulized hypertonic saline

Nebulized heparin

Nebulized tPA

Inhaled Dornase Alfa

Antibiotics

Systemic steroids

Lymphatic embolization

 

25%

92%

79%

75%

29%

8%

33%

54%

46%

13%

8%

 

91%

45%

73%

18%

9%

55%

9%

9%

45%

45%

45%

Adverse Events

No bleeding complications reported

Study Author Conclusions

Optimal therapies for PB remain limited, with treatment varying on a case-by-case basis. Airway clearance using standard chest physiotherapy and/or bronchoscopy is one of the most-utilized therapies in the treatment of PB. Selective lymphatic embolization at centers with appropriate interventional expertise offers a potential new treatment option for patients with PB. Based on our findings, tPA may be more effective on SVHD-related fibrin casts while heparin is better for mucin casts in non-SVHD patients.

InpharmD Researcher Critique

The retrospective nature of the study, as well as the limited sample size, narrows the strength of these findings. Further discussion or details specfically pertaining to inhaled heparin or inhaled alteplase in the sample population were not provided.
References:

Li Y, Williams RJ, Dombrowski ND, et al. Current evaluation and management of plastic bronchitis in the pediatric population. Int J Pediatr Otorhinolaryngol. 2020;130:109799. doi:10.1016/j.ijporl.2019.109799

 

Nebulized alteplase in coronavirus disease 2019 pneumonia: a case series

Design

 Case series

Case presentation 1

A 68-year-old male with a complex medical history, including coronary and peripheral artery disease, chronic kidney failure (eGFR 39.21 mL/min/1.73 m²), hypertension, active multiple myeloma (on velcade, bendamustine, and dexamethasone), hypothyroidism, hyperlipidemia, obstructive sleep apnea, and a 60 pack-year smoking history, presented with a 3-day history of shortness of breath and chest pain.

Upon admission, he was started on oxygen therapy at 4 L/min. Due to worsening respiratory failure and intolerance to non-invasive ventilation (NIV), high-flow nasal cannula (HFNC) support was initiated. Antiplatelet therapy included acetyl salicylic acid (ASA) and ticagrelor.

From days 8 to 12, inhaled alteplase was administered at a dose of 5 mg TID. Following this treatment, inflammatory markers (C-reactive protein [CRP] and interleukin-6 [IL-6]), as well as coagulation-related markers (fibrinogen and d-dimer), showed improvement. HFNC was discontinued on day 13 and replaced with lower-flow oxygen therapy at 3-4 L/min, which was continued through day 21. The patient was then discharged to a rehabilitation clinic.

Case presentation 2

A 51-year-old male with a history of non-Hodgkin's lymphoma (in remission) presented with a one-week history of shortness of breath and loss of smell and taste. He was initiated on extensive NIV therapy with settings of 8 mbar positive end-expiratory pressure (PEEP), 2 mbar pressure support (PS), and 60% oxygen. During breaks from NIV, supplemental oxygen was provided at 8 L/min.

On day 6, d-dimer levels increased to 12.2 μg/mL. A follow-up CT scan ruled out pulmonary embolism but revealed bilateral ground-glass opacities and consolidations. Due to the elevated d-dimer, the enoxaparin dose was increased to 8000 IU twice daily and maintained at that level until discharge.

Inhaled alteplase was administered at 10 mg TID on days 5 and 6, and at 5 mg TID on days 7 through 9. NIV therapy was discontinued on day 10 and replaced with nasal cannula oxygen at 4 L/min, which was stopped on day 13. The patient was then discharged home.
Case presentation 3 

A 66-year-old male with a history of hypertension, prostate cancer, and active urinary cancer was admitted after experiencing five days of fever, shortness of breath, and mild confusion. Initial treatment included oxygen insufflation, followed by the initiation of NIV on day 3. Concurrently, inhaled alteplase was started at a dose of 5 mg TID and continued for five days.

On day 8, NIV was transitioned to HFNC, which was maintained for eight days before being replaced with oxygen via nasal cannula. The patient was discharged home on day 21.
Case presentation 4 

A 63-year-old male with a history of atrial fibrillation, hypertension, type 2 diabetes, severe chronic obstructive pulmonary disease (COPD) on long-term oxygen therapy (2 L/min), and pulmonary hypertension was admitted after five days of shortness of breath. Chest CT revealed ground-glass opacities (GGOs), paraseptal emphysema, a pulmonary mass in the left upper lung, and enlargement of the pulmonary trunk and arteries.

Due to intolerance of NIV, HFNC was initiated. Inhaled alteplase was administered at 5 mg TID for five days. Following admission, inflammatory markers initially improved, but both laboratory values and the patient’s clinical condition progressively worsened. On day 8 of hospitalization, the patient died due to respiratory failure.

Case presentation 5

A 59-year-old male with a history of hypertension and obesity was admitted with shortness of breath and a decline in general condition. Chest CT revealed extensive ground-glass opacities (GGOs) and a small pleural effusion on the left side. HFNC therapy was initiated, followed by NIV.

On day 3, inhaled alteplase was started at 5 mg TID and continued for 3 days. Due to a marked increase in d-dimer levels, a second course of inhaled alteplase was administered 4 days later for an additional 5 days. NIV was discontinued on day 11 and replaced with oxygen insufflation, which was continued through day 31. The patient was discharged on day 34.

Study Author Conclusions

Our findings primarily underscore the possible safety of inhaled alteplase in patients with severe COVID-19 pneumonia. While clinical improvements were observed, these cannot be definitively attributed to alteplase due to the concurrent use of other therapies. Given the encouraging safety profile of inhaled alteplase observed in this study, future research should focus on randomized controlled trials to evaluate its efficacy. These studies should aim to isolate the effects of inhaled alteplase by minimizing the use of concurrent therapies. Additionally, larger-scale studies could help establish standardized dosing regimens and identify specific patient populations that may benefit the most from this treatment. The insights gained from our study can guide the design and implementation of these future investigations.
References:

Milacek C, Stefan AN, Bal C, et al. Nebulized alteplase in coronavirus disease 2019 pneumonia: a case series. J Med Case Rep. 2024;18(1):572. Published 2024 Nov 28. doi:10.1186/s13256-024-04924-2

 

Case series of nebulizing r‐tPA for COVID‐19 induced acute respiratory distress syndrome

Design

  Case series

Case presentation 1

A 47-year-old woman with a history of hypertension presented with a 7-day history of dry cough, fatigue, fever, and myalgia. On arrival to the emergency department, she was febrile (41°C), tachycardic, tachypneic, and hypoxic (SpO₂ 80% on room air). Chest CT revealed bilateral peripheral ground-glass opacities and consolidations, suggestive of COVID-19 pneumonia. Labs showed anemia (hemoglobin 6.6 g/dL, MCV 61 fl), lymphopenia, elevated CRP, ESR, and LDH.

She was admitted and started on oxygen via reservoir mask, anticoagulation, broad-spectrum antibiotics, hydroxychloroquine, and lopinavir/ritonavir. Her respiratory status worsened, requiring escalation to imipenem and eventually intubation following further oxygen desaturation. Methylprednisolone 250 mg IV was given after intubation. On hospital day 6, nebulized recombinant tissue plasminogen activator (r-tPA) was administered. Oxygenation improved over the next 24 hours, with SpO₂ rising from 88% to 96% on a constant FiO₂ of 60%. Unfortunately, prior to the second dose of nebulized r-tPA, the patient developed seizures and upward gaze, prompting discontinuation of r-tPA and imipenem, and initiation of antiepileptic therapy. A brain CT could not be performed due to her critical condition. Although no further seizure activity was observed, her oxygen saturation began to decline the day after r-tPA administration. Despite continued care, the patient ultimately died nine days later from asystole following 45 minutes of cardiopulmonary resuscitation.

Case presentation 2

A 78-year-old man with diabetes and hypertension presented with a one-week history of dry cough, fever, and dyspnea. On arrival to the emergency department, he was hypoxic (SpO₂ 78%), tachypneic, and tachycardic. Chest CT confirmed COVID-19 pneumonia, and laboratory tests showed lymphopenia and elevated CRP and ESR.

He was started on pressure support ventilation, prophylactic heparin, methylprednisolone, hydroxychloroquine, and lopinavir/ritonavir. Despite treatment, his respiratory status worsened, and he was intubated on hospital day 14 due to severe hypoxemia. On day 18, nebulized r-tPA was initiated due to persistently low SpO₂ (80% on 100% FiO₂). Three doses were given on consecutive days, each resulting in temporary improvement, with SpO₂ reaching 91% after the third dose. However, oxygenation subsequently declined, and he developed ventilator-associated pneumonia with resistant organisms. Despite maximal supportive care, he died on hospital day 38 following 45 minutes of cardiopulmonary resuscitation.

Case presentation 3

A 65-year-old woman with a history of diabetes and anemia presented with exertional dyspnea and fatigue. On arrival to the emergency department, she was tachypneic with an SpO₂ of 85% on room air. Imaging and PCR confirmed COVID-19 pneumonia. Laboratory abnormalities included lymphopenia, elevated CRP, ESR (107 mm/h), and LDH (1249 U/L).

She was admitted to the COVID-19 ward and started on hydroxychloroquine, sofosbuvir/daclatasvir, prophylactic heparin, and CPAP. However, she did not tolerate CPAP, and oxygenation continued to decline. She received methylprednisolone, thiamine, and high-dose vitamin C. On hospital day 13, nebulized r-tPA was initiated. SpO₂ improved from 85% to a peak of 98% over three days, but fell to 77% the day after r-tPA was stopped. She experienced respiratory arrest on day 23 and was intubated. Despite resuscitation efforts, she died from asystole on day 25 after 45 minutes of CPR.

Study Author Conclusions

In all three cases, we have seen improvement in SF ratio as an oxygenation index. However, the effect of treatment was short lasting and after stopping r‐tPA nebulization these effects vanished. In the first case, nebulization led to +9% changes at the end of the day. The second case, showed +10%, +22%, and 13% improvement compared with baseline after each dose, respectively. Continuous improvement was seen in the third case, as +4.7%, +8.2%, and +15.2% variation occurred after every nebulization. However, by discontinuing the treatment, fall in SF ratio in all cases was detected.
References:

Amini S, Labbani-Motlagh Z, Aliannejad R, Pourabbas SM, Vasei M. Case series of nebulizing r-tPA for COVID-19 induced acute respiratory distress syndrome. Clin Case Rep. 2022;10(9):e6283. Published 2022 Sep 5. doi:10.1002/ccr3.6283