A Breath of Fresh Air: Nebulized TXA for Hemoptysis

An 80-year-old male arrived at the Emergency Department (ED) in a serious condition: he was coughing up blood. Although he coughed up about three tablespoons (50cc/hr), he was hemodynamically stable. A physician approached me with an unfamiliar question: “Could we give him nebulized TXA?” I looked at him for a moment, nonplussed. “What?!” I exclaimed, “Hold on—let me look it up and get back to you.” Questions flooded my mind: Is it effective? Is it safe? If so, what is the appropriate dosage? 

Hemoptysis, defined as the expectoration of blood, alone or mixed with mucus, is a common symptom encountered in the ED.[ 1] In most cases, hemoptysis is a self-limiting condition. In others, it may become a life-threatening condition that warrants urgent investigation and treatment. [2] Although the choice of a cutoff value is controversial, the method of distinguishing between “massive” and “non-massive” hemoptysis involves measuring the volume of blood expectorated over a period of 24 hours; some sources cite the amount that has to be coughed up for the hemoptysis to count as “massive” to be in the 100 mL to 1000 mL range. However, no specific volume has been accepted universally. It is worth noting that the volume of blood is not solely indicative of massive hemoptysis; rather, it is the continuous bleeding which causes life-threatening conditions such as abnormal gas exchange or hemodynamic instability.[3] 

An invasive procedure may be required to control hemoptysis; this generally lies outside the scope of emergency medicine.[1] Thus, management of hemoptysis in the ED primarily focuses on airway protection, reversal of coagulopathies, supportive care, and investigation of the bleeding site, after which one may guide the patient toward other definitive treatment measures. Tranexamic acid (TXA) is a synthetic derivative of lysine.[4] It acts as an inhibitor of fibrinolysis by blocking the lysine-binding site of plasminogen to fibrin. The drug has been widely used to promote hemostasis during surgery or in cases of inner organ bleeding. Its use has been steadily increasing and multiple studies have shown it to be effective in treating non-massive hemoptysis, whether given orally or intravenously. However, few studies have described the potential benefits of using TXA as a nebulizer to control hemoptysis save for a randomized controlled trial that was published in October of this year. 

A number of case reports have demonstrated nebulized TXA to be both safe and effective.[5, 6] Each of the two cases detailed a scenario of patients presented to the ED suffering from massive hemoptysis and mild respiratory distress. 1000 mg of nebulized TXA was diluted with 0.9% normal saline to form either a 10 mg/mL or 50 mg/mL solution. The bleeding ceased within 10 to 15 minutes of administration with no recurring episodes of hemoptysis. Moreover, a total of three case series examining the effects of inhaled TXA as a nebulizer to control hemoptysis have been published.[7, 8, 9] In the first series, four patients were presented to the ED with hemoptysis: one of them suffered from a massive hemoptysis of 500 mL while no volume was reported for the other three patients.[7] Their conditions were managed with aerosolized TXA (500mg administered four times daily). TXA caused a rapid cessation of bleeding. In a second series, four patients with moderate hemoptysis (mean blood volume of 100 mL/ day) were treated with 250 to 500mg doses every 8 hours of TXA via nebulizer with a flow rate of 5 L of oxygen per minute.[8] The treatment resulted in successful bleeding cessation in all cases. There was a caveat, however: researchers noted that one patient experienced a bronchospasm after three doses of TXA. In the third case series, it was reported that a series of two patients with acute massive hemoptysis were treated with nebulized TXA in doses of 500 mg every 8 hours.[9] Both patients experienced a complete cessation of bleeding within a 48 to 72-hour period. 

In 2010, a group of investigators from Spain published a two-year prospective observational trial that tested endobronchial TXA as a treatment for moderate hemoptysis in patients who failed to respond to either topical adrenaline or ice-cold saline lavage.[10] The study included patients whose bleeding rates ranged from 50-100 mL/hr for patients with normal lung function or from 25-50 mL/hr for patients with chronic lung failure. 

The bleeding was categorized into two groups: the iatrogenic group, composed of patients whose bleeding was a result of bronchoscopy (regardless of the amount of blood), and the non-iatrogenic group, made up of those patients suffering from spontaneous bronchial bleeding (> 200 mL within a 24-hour period).[10] TXA was administered via endobronchial instillation in doses of 500 mg; it was diluted with 15mL normal saline. A total of 48 patients were treated with TXA; 20 were in the iatrogenic group and 28 in the non-iatrogenic group. All 20 patients in the iatrogenic group successfully responded to TXA and 11 out of 28 patients in the non-iatrogenic group responded to the treatment (39.2%). In terms of safety, none of the subjects in either patient group suffered from thrombosis or otherwise adverse events related to TXA. 

A recent prospective, double-blind, placebo-controlled, randomized controlled trial (RCT) was conducted to evaluate the efficacy of TXA as nebulizer for hemoptysis.[11] Patients were excluded if they presented with more than 200 mL of expectorated blood over 24 hours, hemodynamic instability, renal failure, or hepatic failure. Antiplatelet and anticoagulant agents were held until the hemoptysis was resolved. Patients received either 500 mg of nebulized TXA or a placebo (5 mL of 0.9% normal saline) three times daily for up to 5 days from date of admission. A total of 47 patients were randomly assigned to receive either TXA (25 patients) or a placebo (22 patients). The study showed that nebulized TXA resulted in complete resolution of hemoptysis within 5 days in 96% of patients in the TXA group versus 50% in the placebo group. From the second day of admission, those who were administered nebulized TXA experienced a marked reduction in bleeding levels compared to those patients in the placebo group. Notably, the length of stay was also shorter for those in the TXA group vs. placebo group by an average of 2.1 days. In terms of safety, no adverse effects were reported from either group. 

TXA has a number of minor side effects including nausea, headache, and musculoskeletal pain.[4] Another potential concern is the theoretical risk of arterial and venous thrombosis based on its mechanism of action. Although multiple trials have showed no increase in the risk for thrombosis with systemic administration of TXA, seizure did occur in one case. Apart from seizure (<1%), no other major side effects have been reported.  Based on published RCTs, observational trial, case series, and case reports, only one instance of bronchospasm was reported. 

We can safely conclude that nebulized TXA administration via inhalation is a successful treatment with few to nil adverse effects.[4] It can rapidly control hemoptysis and serves as a palliative option in treating chronic hemoptysis.  It also serves as a viable form of bridging therapy for hemodynamically stable patients to avoid endotracheal intubation until other definitive therapies can be arranged. The dosage for nebulizer use ranges from 250-500 mg every 6 to 8 hours or 1000 mg as a single dose.[4,6]  
 

Raniah Aljadeed, PharmD

PGY2 Emergency Medicine Pharmacy Resident
University of Arizona College of Pharmacy 
Northwest Medical Center


Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

References: 

  1. Ittrich H, Bockhorn M, Klose H, et al. The Diagnosis and Treatment of Hemoptysis. Dtsch Arztebl Int. 2017 Jun; 114(21): 371–381. 
  2.  Larici AR, Franchi P, Occhipinti M, et al. Diagnosis and management of hemoptysis. Diagn Interv Radiol. 2014 Jul-Aug; 20(4): 299–309. 
  3. WH Ibrahim. Massive haemoptysis: the definition should be revised. Eur Respir J. 2008 Oct; 32(4):1131-2.  
  4. Gadre A, Stoller JK. Tranexamic acid for hemoptysis: a review. Clin Pulm Med. 2017; 24(2):69-74. 
  5. Hankerson MJ, Raffetto B, Mallon WK, et al. Nebulized Tranexamic Acid as a Noninvasive Therapy for Cancer-Related Hemoptysis. J Palliat Med. 2015 Dec; 18(12):1060-2. 
  6. Komura S, Rodriguez RM, Peabody CR. Hemoptysis? Try Inhaled Tranexamic Acid. J Emerg Med. 2018 May; 54(5):e97-e99.  
  7. Solomonov A, Fruchter O, Zuckerman T, et al. Pulmonary hemorrhage: A novel mode of therapy. Respir Med. 2009 Aug; 103(8):1196-200. 
  8. Segrelles Calvo G, De Granda-Orive I, Lopez Padilla D. Inhaled tranexamic acid as an alternative for hemoptysis treatment. Chest. 2016; 149:604. 
  9.  Patel M, Abbas F, Sheppard T. 1887: hemoptysis controlled with the use of inhaled tranexamic acid: a case series. Crit Care Med. 2016; 44(suppl 1):547. 
  10. Márquez-Martín E, Vergara DG, Martín-Juan J, et al. Endobronchial administration of tranexamic Acid for controlling pulmonary bleeding: a pilot study. J Bronchology Interv Pulmonol. 2010 Apr; 17(2):122-5. 
  11. Wand O, Guber E, Guber A, et al. Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial.  Chest. 2018 Oct 12.

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