Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago
SYNOPSIS: A pragmatic, open-label, randomized, parallel, single-center pilot trial investigating nebulized vs. intravenous tranexamic acid in patients with non-massive hemoptysis showed that nebulized tranexamic acid may be more effective in reducing the amount of hemoptysis and the need for interventional procedures.
SOURCE: Gopinath B, Mishra PR, Aggarwal P, et al. Nebulized vs IV tranexamic acid for hemoptysis: A pilot randomized controlled trial. Chest 2023;163:1176-1184.
It is unknown whether intravenous (IV) or nebulized tranexamic acid (TXA) is the best strategy to control hemoptysis in patients who present to the emergency department (ED). Gopinath and colleagues performed a pragmatic, open-label, randomized, parallel, single-center pilot trial in an academic ED in India. Between July 2019 and December 2021, 110 adult patients who experienced active hemoptysis, defined as blood in sputum in the last 30 minutes of the patient presenting to the ED, were randomly assigned by block randomization to nebulized TXA (500 mg three times daily) vs. IV TXA (500 mg three times daily). The primary outcome was cessation of bleeding at 30 minutes. Secondary outcomes included need for interventional procedures, side effects of TXA, and amount of hemoptysis at six, 12, and 24 hours. Exclusion criteria included patients who were hemodynamically unstable, those requiring mechanical ventilation, or those in need of an immediate interventional procedure.
At 30 minutes, hemoptysis cessation was significantly higher in the nebulized TXA arm (n = 40) compared with the IV TXA arm (n = 28): X2 (1, n = 110) = 5.55; P = 0.0019. The amount of hemoptysis also was significantly reduced in the nebulization arm at all time periods of observation (P value at 30 minutes = 0.011, at six hours = 0.002, at 12 hours = 0.0008, and at 24 hours = 0.005). The TXA nebulization arm required less bronchial artery embolization intervention (13 vs. 21; P = 0.024) with higher discharge rates from the ED (67.92% vs. 39.02%; P = 0.005) when compared to IV TXA.
As for complications, two patients in the nebulization arm had asymptomatic bronchoconstriction that resolved after short-acting beta-agonist nebulization. Within the 72-hour follow-up period, no patients discharged from the ED revisited the ED with rebleed or underwent any interventional procedure. This clinical trial revealed that nebulized TXA may be more efficacious than IV TXA in decreasing the amount of hemoptysis and need for ED interventional procedures.
COMMENTARY
Hemoptysis is a medical emergency that may be life-threatening. The reported mortality rate for life-threatening hemoptysis is between 9% and 38%.1 Resuscitation and stabilization are critical first steps in the initial management. TXA, a potent antifibrinolytic drug that prevents degradation of fibrin, has been found to be effective in reducing blood loss following trauma, in the treatment of heavy vaginal bleeding, and in the perioperative management of major surgery.2 More specifically, TXA not only forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis, but also inhibits the proteolytic activity of plasmin.
Until 2016, the data on TXA and hemoptysis were debated but were noted to be successful in numerous smaller manuscripts. In 2016, a single-blinded, prospective study revealed that IV TXA decreased the severity of hemoptysis and that it was effective as a bridging therapy while awaiting a more definitive intervention.3
Although IV formulations of TXA were effective, inhaled TXA also was appealing because it had the potential to have more rapid onset of action at the site of bleeding because of its noninvasive, almost immediate administration. Of course, the question of whether nebulized TXA was better than IV TXA alone sparks an interesting clinical question, especially since there was a paucity of data comparing the specific route of administration of TXA. In 2018, a double-blind, randomized controlled trial of treatment with nebulized TXA (500 mg three times daily) vs. placebo (normal saline) proved that inhaled TXA was associated with successful reduction in expectorated blood volume, resolution of hemoptysis, reduced hospital length of stay, fewer invasive procedures without side effects, and reduced recurrence at one-year follow-up for non-massive hemoptysis treatment.4 This was one of the first studies to show that TXA inhalation can be used safely and effectively to control bleeding in patients with non-massive hemoptysis. Although it was known that inhaled TXA was safe and effective, data supporting its use over IV TXA were not available.
Although more studies are needed, Gopinath and colleagues were one of the first groups to conduct a pragmatic, open-label, randomized, parallel, single-center pilot trial comparing nebulized TXA to IV TXA and showed that nebulized TXA may be more efficacious than IV TXA since investigators were able to show that hemoptysis cessation at 30 minutes was significantly higher in the nebulized TXA group (72.72%) compared with the IV TXA group (50.91%).
The important aspect of this study is that it was conducted in India with tuberculosis as the most common etiology of hemoptysis (76.36%), followed by allergic bronchopulmonary aspergillosis (ABPA) (26.36%). Lung malignancy only represented 7.27% of cases. Although tuberculosis is the most common cause of hemoptysis in developing countries, malignancy along with bronchitis and bronchiectasis are the primary underlying etiologies in developed countries.5 For example, in a teaching hospital in Italy, researchers conducted a retrospective review of the clinical records of patients who presented with hemoptysis and found the most common diagnosis was lung malignancy (19%), but tuberculosis only represented 4% of all cases. In contrast to the Gopinath study, the etiology of hemoptysis remained undetermined in one-third of these patients.6 It is important to note that cryptogenic hemoptysis also may be a harbinger for underlying malignancy, especially since malignancy can lead to hemoptysis via several etiologies, including neo-vascularization within the mass, tumor necrosis, erosion into the central airways and surrounding vessels, and/or cavitation of the mass.7 One particular study revealed that 6% of the patients with cryptogenic hemoptysis developed lung cancer, with the diagnosis finally revealed approximately 17.3 months after initial presentation.
These studies stress the importance that one may need to be cautious in applying the effectiveness of TXA found in this study to all patient populations but also stresses that follow-up is critical if the etiology of hemoptysis is not known. It also is important to note that the median volume of hemoptysis in the study was about 100 mL/day and the efficacy of nebulized TXA is unknown at higher volumes.
This pilot study supports the use of nebulized TXA for non-massive hemoptysis because nebulized TXA may be more efficacious than IV TXA in decreasing the amount of hemoptysis. In the future, it would be of great interest to conduct larger randomized controlled trials that would be able to evaluate a more diverse patient population over a prolonged period of time and explore the differences in outcomes between those patients with massive and sub-massive hemoptysis.
REFERENCES
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- Mannucci PM. Hemostatic drugs. N Engl J Med 1998;339:245-253.
- Bellam BL, Dhibar DP, Suri V, et al. Efficacy of tranexamic acid in haemoptysis: A randomized, controlled pilot study. Pulm Pharmacol Ther 2016;40:80-83.
- Wand O, Guber E, Guber A, et al. Inhaled tranexamic acid for hemoptysis treatment: A randomized controlled trial. Chest 2018;154:1379-1384.
- Charya AV, Holden VK, Pickering EM. Management of life-threatening hemoptysis in the ICU. J Thorac Dis 2021;13:5139-5158.
- Vanni S, Bianchi S, Bigiarini S, et al. Management of patients presenting with haemoptysis to a tertiary care Italian emergency department: The Florence Haemoptysis Score (FLHASc). Intern Emerg Med 2018;13:397-404.
- Gershman E, Guthrie R, Swiatek K, Shojaee S. Management of hemoptysis in patients with lung cancer. Ann Transl Med 2019;7:358.
A pragmatic, open-label, randomized, parallel, single-center pilot trial investigating nebulized vs. intravenous tranexamic acid in patients with non-massive hemoptysis showed that nebulized tranexamic acid may be more effective in reducing the amount of hemoptysis and the need for interventional procedures.
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