What literature is available for the use of inhaled tranexamic acid in hemoptysis?
Introduction
Hemoptysis refers to the expectoration of blood from the respiratory tract.1 Hemoptysis can arise from bleeding anywhere in the respiratory tract, including the trachea, bronchi, or pulmonary parenchyma.1,2 Depending on the anatomical source of the bleeding and the underlying cause, the presentation of hemoptysis can range from light streaks of blood in expectorated sputum to large amounts of frank blood.2
Massive hemoptysis (also referred to as pulmonary hemorrhage) is the most severe form of hemoptysis: historically, it has been differentiated from non-massive hemoptysis by the volume of blood expectorated, but the volume of blood expectorated is often difficult to measure or estimate, and no precise differentiating volume has ever been agreed upon in the medical literature.1,3 Therefore, massive hemoptysis can also be defined as any degree of hemoptysis that causes significant clinical consequences, such as hypotension or respiratory failure due to airway obstruction.3 Massive hemoptysis is life-threatening: prior to the development of modern interventional techniques, mortality with massive hemoptysis was over 75%. When appropriate management strategies are initiated in a timely manner, mortality rates are reduced to 13% to 17.8%.
Physiology and Etiology of Hemoptysis
Bleeding in the respiratory tract can arise from either the pulmonary circulation or the bronchial circulation.1 Pulmonary arteries are low-pressure vessels, while bronchial arteries are part of the high-pressure systemic circulation; massive hemoptysis is therefore more likely to originate from the bronchial arteries.1,2 A number of disease states have been associated with hemoptysis, including pulmonary infection, bronchitis, bronchiectasis, tuberculosis, bronchogenic carcinoma, pulmonary edema, and pulmonary embolism.1 Bronchial arteries can proliferate in the setting of chronic inflammation, resulting in the presence of abnormal vessels that are highly prone to bleeding.2 Tumors can also cause the proliferation of blood vessels in the lungs, or erode into pulmonary blood vessels that are already present.1,4
Management of Hemoptysis
Management of hemoptysis depends on the severity of the bleeding and the underlying etiology.1 Patients who present with hemoptysis should be assessed for signs of hemodynamic instability and respiratory distress, including dyspnea, hypoxemia, tachypnea, tachycardia, and hypotension.1,2 If the patient is stable and experiencing small, non-massive hemoptysis, they can be evaluated on an outpatient basis.1 Chest imaging should be performed to determine the underlying cause of hemoptysis; bronchoscopy may also be indicated to rule out bronchogenic carcinoma. In many cases, treating the underlying cause of hemoptysis (eg, infection) will resolve the symptoms.2 However, if bleeding persists, additional intervention may be required.
Patients with massive hemoptysis are at risk for asphyxiation due to blood in the airway, and must be treated as early as possible.1,2 Immediate goals of therapy in massive hemoptysis are to protect the lung that is not bleeding, locate the site of the bleeding, and control bleeding.1 The patient should be positioned with the bleeding side down, if the bleeding side is known; this prevents blood from going into the non-bleeding lung. If intubation is required, it should be done in a way that protects the non-bleeding lung and enables passage of flexible bronchoscopes through the endotracheal tube.3 The source of the bleeding may be identified via CT scan or bronchoscopy. Bronchoscopy is also useful for managing bleeding, once the source of bleeding is found; bronchoscopy allows for the removal of blood clots, placement of bronchial blockers, and direct instillation of medications (such as cold saline, epinephrine, or norepinephrine). Additionally, it can allow for the administration of local thermoablative therapies, such as electrocautery, laser therapy, and argon plasma coagulation. Other methods to control bleeding at the site include the use of oxidized regenerated cellulose, gelatin-thrombin, silicone spigots, airways stents, and polymer surgical sealants. Tranexamic acid can also be administered. Once hemostasis is achieved, most patients with massive hemoptysis must subsequently receive definitive therapy. Most often, this takes the form of bronchial artery embolization. Surgical management is typically reserved for patients whose bleeding cannot be controlled with other therapies, but it may be considered a first-line intervention in some circumstances (for example, when hemoptysis is related to iatrogenic pulmonary artery rupture or complex arteriovenous malformations).
Evidence for Inhaled Tranexamic Acid in Hemoptysis
Tranexamic acid is a lysine derivative that blocks lysine-binding sites on plasminogen and thus inhibits fibrinolysis.5 Most commonly, tranexamic acid is used intravenously or orally in the management of hemoptysis; however, a limited number of reports have explored the use of tranexamic acid as a nebulized solution or endobronchial instillation. These reports are summarized in Table 1.6-13 Varying dosing regimens have been used; some patients have received larger one-time doses of 1 to 2 g, while others have received doses of 250 to 500 mg every 6, 8, or 12 hours. Dilutions also varied, although many reports appeared to use the intravenous solution at the commercially available concentration of 100 mg/mL.6-14 Administration of nebulized tranexamic acid generally led to successful resolution of hemoptysis; in some cases, patients experienced relief after the first dose, but other patients required multiple doses, and one patient required prolonged treatment to prevent recurrence of hemoptysis.
Although most evidence for nebulized tranexamic acid in hemoptysis comes from case reports, a randomized, double-blind trial of 47 patients with hemoptysis compared the effect of nebulized tranexamic acid 500 mg 3 times daily to that of a nebulized saline placebo.6 In this trial, more patients in the tranexamic acid group achieved resolution of bleeding within 5 days of admission (96% vs. 50%; p less than 0.0005). The length of stay was shorter in the tranexamic acid group by about 2 days, and no patients in the tranexamic acid group required interventional procedures to control bleeding. Interventional procedures were required in 4 patients in the placebo group (2 patients required interventional bronchoscopy, and 2 patients required urgent angiographic embolization). At 1 year, patients who received tranexamic acid had lower rates of hemoptysis recurrence (4% vs 22.7%), but mortality rates were not significantly different between groups. Of note, this trial excluded patients with massive hemoptysis (defined as >200 mL expectorated blood over 24 hours), hemodynamic instability, or respiratory instability. Therefore, the results of this trial may not be applicable to patients with more severe presentations of hemoptysis.
| Table 1. Summary of reports describing inhaled tranexamic acid for hemoptysis.6-13 | |||
|---|---|---|---|
| Citation | Patient(s) | TXA Preparation/Dosing | Outcome |
| Randomized controlled trial | |||
| Wand 20186 Randomized, double-blind, placebo-controlled trial | 47 adult patients with hemoptysis of varying etiology (bronchiectasis, n=16; malignancy, n=17; infection, n=5; COPD, n=3; unknown, n=6) 27 patients were taking anticoagulants or antiplatelets Patients with massive hemoptysis (>200 mL in 24 hours), hemodynamic instability, or respiratory instability were excluded | Nebulized TXA 500 mg/5 mL given 3 times daily (n=25) Nebulized normal saline (5 mL) given 3 times daily (n=22) | Primary outcomes: Resolution of bleeding was achieved during the first 5 days of admission in 96% of patients receiving TXA and 50% of patients receiving placebo (p<0.0005) TXA was associated with a significantly reduced amount of expectorated blood, starting from day 2 of admission Secondary outcomes: Fewer interventional procedures were required to control bleeding in the TXA group (0% vs. 18.2%; p=0.041) Hospital length of stay was shorter in patients who received TXA (mean of 5.7 days vs. 7.8 days; p=0.046) Rate of recurrent hemoptysis at 1 year was significantly lower in the TXA group (4% vs 22.7%; p<0.01), but there were no significant differences in mortality between groups |
| Case reports | |||
| Dhanani 20207 Case report | 65-year-old male with hemoptysis secondary to submassive PE; mild to moderate hemoptysis persisted at day 5 despite supportive care for hypoxic respiratory failure, so nebulized TXA was initiated | TXA 500 mg in 5 mL normal saline administered via jet nebulizer with 5 L/min oxygen flow rate Delivered over 15 minutes Repeated every 6 hours for 4 doses | Hemoptysis resolved after 2 doses of inhaled TXA, no local or systemic side effects were observed Therapeutic heparin was started 12 hours after cessation of hemoptysis and no recurrence of hemoptysis was noted. Patient was discharged on day 15 on warfarin therapy |
| Sanghvi 20198 Case report | 78-year-old female with pulmonary hemorrhage secondary to tPA administration for stroke Bleeding began after endotracheal intubation (300 mL over first 20 minutes) | Nebulized TXA 2 g over 20 minutes | Bleeding ceased after administration of inhaled TXA; approximately 400 mL blood loss occurred in total Patient was extubated on day 3 and discharged on day 10 |
| Komura 20189 Case report | 69-year-old female with stage IV lung carcinoma presenting with 1 day of multiple episodes of hemoptysis after receiving chemotherapy the previous day Within 1 hour of presentation, hemoptysis increased and respiratory distress worsened Patient also had a history of PE, and was taking rivaroxaban | Nebulized TXA 1 g in 20 mL normal saline | Within 10 minutes of TXA administration, hemoptysis resolved and respiratory distress improved No further episodes of hemoptysis were reported; patient was discharged after 5 days |
| Gonzalez-Castro 201810 Case report | 18-year-old male with idiopathic pulmonary hemosiderosis presenting with hemoptysis and respiratory failure requiring intubation and mechanical ventilation Nebulized TXA was initiated on day 3, as clinical status continued to worsen | Nebulized TXA 500 mg/5mL every 12 hours | Patient’s status improved, with no new episodes of bleeding or anemia; patient was extubated on day 9 |
| Segrelles Calvo 201611 Case series | 4 male patients with moderate hemoptysis secondary to lung cancer (n=3) or bronchiectasis (n=1) | TXA 500 mg/5mL, given at a dose of 250 mg every 8 hours (n=1), 250 mg every 12 hours (n=1), or 500 mg every 8 hours (n=2) via jet nebulizer with 5 L/min oxygen flow rate Average duration of nebulization was 15 minutes | Hemoptysis resolved within 6 to 48 hours of starting TXA Bronchospasm was observed in 1 patient, but no other local or systemic adverse effects were observed |
| Hankerson 201512 Case report | 46-year-old male with stage IV sinus and thyroid squamous cell carcinoma presenting with hemoptysis per tracheostomy tube and moderate respiratory distress | TXA 1 g in 100 mL normal saline nebulized over 30 to 45 minutes | Hemoptysis resolved over 15 minutes with TXA nebulization and did not recur while the patient was in the emergency department Patient was admitted for observation and evaluation for bronchial artery embolization |
| Solomonov 200913 Case series | 6 patients with uncontrolled pulmonary hemorrhage 4 patients had unidentifiable sources of bleeding and were treated with inhaled TXA, while 2 patients had identifiable sources of bleeding and were treated with TXA instilled via bronchoscope | Inhaled TXA 500 mg/5 mL was given at doses of 500 mg 4 times daily (n=3) or 500 mg 4 times daily, then 250 mg 2 to 3 times daily (n=1) Treatment durations were 2 days, 3 days, 1 week, and 3 months When TXA was administered via bronchoscope, single doses of 500 mg/5 mL were given | Hemoptysis resolved with the first dose of inhaled TXA in all patients One patient receiving inhaled TXA had recurrence of hemoptysis when TXA was stopped after 72 hours; this patient was continued on preventive therapy with inhaled TXA 250 mg 2 to 3 times daily for 3 months before gradually tapering off therapy |
| Abbreviations: COPD=chronic obstructive pulmonary disease; PE=pulmonary embolism; tPA=tissue plasminogen activator; TXA=tranexamic acid. | |||
Conclusion
Nebulized tranexamic acid has been effective for controlling hemoptysis in several case reports and 1 small randomized controlled trial. More data are needed to confirm the utility of nebulized tranexamic acid in patients with massive hemoptysis and hemodynamic or respiratory instability, as these patients were excluded from the sole randomized controlled trial that has been conducted. However, based on limited evidence, nebulized tranexamic acid may be a useful tool in the management of hemoptysis. Various dosing regimens and dilutions of tranexamic acid have used: in the randomized controlled trial, tranexamic acid 500 mg/5 mL was given every 8 hours. Intravenous tranexamic acid is commercially available as a 100 mg/mL solution, and many reports used this concentration; in some reports, this solution was diluted with normal saline for nebulization.
References
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- Knudson C, Chaiyachati S, Velasquez A. Hemoptysis. In: McKean SC, Ross JJ, Dressler DD, Scheurer DB, eds. Principles and Practice of Hospital Medicine. 2nd ed. New York, NY: McGraw-Hill; 2017. http://accessmedicine.mhmedical.com/content.aspx?bookid=1872§ionid=146976678. Accessed February 13, 2020.
- Davidson K, Shojaee S. Managing massive hemoptysis. Chest. 2020;157(1):77-88.
- Simoff MJ, Lally B, Slade MG, et al. Symptom management in patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e455S-e497S.
- Gagnon S, Quigley N, Dutau H, Delage A, Fortin M. Approach to hemoptysis in the modern era. Can Respir J. 2017;2017:1565030.
- Wand O, Guber E, Guber A, Epstein Shochet G, Israeli-Shani L, Shitrit D. Inhaled tranexamic acid for hemoptysis treatment: a randomized controlled trial. Chest. 2018;154(6):1379-1384.
- Dhanani JA, Roberts J, Reade MC. Nebulized tranexamic acid therapy for hemoptysis associated with submassive pulmonary embolism. J Aerosol Med Pulm Drug Deliv. 2020;33(1):12-14.
- Sanghvi S, Van Tuyl A, Greenstein J, Hahn B. Tranexamic acid for treatment of pulmonary hemorrhage after tissue plasminogen activator administration for intubated patient. Am J Emerg Med. 2019;37(8):1602.e1605-1602.e1606.
- Komura S, Rodriguez RM, Peabody CR. Hemoptysis? Try inhaled tranexamic acid. J Emerg Med. 2018;54(5):e97-e99.
- Gonzalez-Castro A, Rodriguez-Borregan JC, Chicote E, Escudero P, Ferrer D. Nebulized tranexamic acid as a therapeutic alternative in pulmonary hemorrhage. Arch Bronconeumol. 2018;54(8):442-443.
- Segrelles Calvo G, De Granda-Orive I, Lopez Padilla D. Inhaled tranexamic acid as an alternative for hemoptysis treatment. Chest. 2016;149(2):604.
- Hankerson MJ, Raffetto B, Mallon WK, Shoenberger JM. Nebulized tranexamic acid as a noninvasive therapy for cancer-related hemoptysis. J Palliat Med. 2015;18(12):1060-1062.
- Solomonov A, Fruchter O, Zuckerman T, Brenner B, Yigla M. Pulmonary hemorrhage: A novel mode of therapy. Respir Med. 2009;103(8):1196-1200.
- Clinical Pharmacology [database online]. Tampa, FL: Elsevier, Inc; 2020. http://clinicalpharmacology.com/. Accessed February 21, 2020.
Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
March 2020
The information presented is current as of February 7, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.